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Wu JG, Zhou CP, Gui WW, Liang ZY, Zhang FB, Fu YG, Li R, Wu F, Lin XH. Correlation of IGF2 levels with sperm quality, inflammation, and DNA damage in infertile patients. Asian J Androl 2025; 27:204-210. [PMID: 39468803 PMCID: PMC11949453 DOI: 10.4103/aja202487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 08/30/2024] [Indexed: 10/30/2024] Open
Abstract
ABSTRACT Insulin-like growth factor 2 (IGF2) is a critical endocrine mediator implicated in male reproductive physiology. To investigate the correlation between IGF2 protein levels and various aspects of male infertility, specifically focusing on sperm quality, inflammation, and DNA damage, a cohort of 320 male participants was recruited from the Women's Hospital, Zhejiang University School of Medicine (Hangzhou, China) between 1 st January 2024 and 1 st March 2024. The relationship between IGF2 protein concentrations and sperm parameters was assessed, and Spearman correlation and linear regression analysis were employed to evaluate the independent associations between IGF2 protein levels and risk factors for infertility. Enzyme-linked immunosorbent assay (ELISA) was used to measure IGF2 protein levels in seminal plasma, alongside markers of inflammation (tumor necrosis factor-alpha [TNF-α] and interleukin-1β [IL-1β]). The relationship between seminal plasma IGF2 protein levels and DNA damage marker phosphorylated histone H2AX (γ-H2AX) was also explored. Our findings reveal that IGF2 protein expression decreased notably in patients with asthenospermia and teratospermia. Correlation analysis revealed nuanced associations between IGF2 protein levels and specific sperm parameters, and low IGF2 protein concentrations correlated with increased inflammation and DNA damage in sperm. The observed correlations between IGF2 protein levels and specific sperm parameters, along with its connection to inflammation and DNA damage, underscore the importance of IGF2 in the broader context of male reproductive health. These findings lay the groundwork for future research and potential therapeutic interventions targeting IGF2-related pathways to enhance male fertility.
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Affiliation(s)
- Jing-Gen Wu
- Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Cai-Ping Zhou
- Department of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Wei-Wei Gui
- Department of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Zhong-Yan Liang
- Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Feng-Bin Zhang
- Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Ying-Ge Fu
- Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Rui Li
- Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Fang Wu
- Department of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Xi-Hua Lin
- Department of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
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Starr AL, Nishimura T, Igarashi KJ, Funamoto C, Nakauchi H, Fraser HB. Disentangling cell-intrinsic and extrinsic factors underlying evolution. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.06.592777. [PMID: 38798687 PMCID: PMC11118348 DOI: 10.1101/2024.05.06.592777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
A key goal of developmental biology is to determine the extent to which cells and organs develop autonomously, as opposed to requiring interactions with other cells or environmental factors. Chimeras have played a foundational role in this by enabling qualitative classification of cell-intrinsically vs. extrinsically driven processes. Here, we extend this framework to precisely decompose evolutionary divergence in any quantitative trait into cell-intrinsic, extrinsic, and intrinsic-extrinsic interaction components. Applying this framework to thousands of gene expression levels in reciprocal rat-mouse chimeras, we found that the majority of their divergence is attributable to cell-intrinsic factors, though extrinsic factors also play an integral role. For example, a rat-like extracellular environment extrinsically up-regulates the expression of a key transcriptional regulator of the endoplasmic reticulum (ER) stress response in some but not all cell types, which in turn strongly predicts extrinsic up-regulation of its target genes and of the ER stress response pathway as a whole. This effect is also seen at the protein level, suggesting propagation through multiple regulatory levels. Applying our framework to a cellular trait, neuronal differentiation, revealed a complex interaction of intrinsic and extrinsic factors. Finally, we show that imprinted genes are dramatically mis-expressed in species-mismatched environments, suggesting that mismatch between rapidly evolving intrinsic and extrinsic mechanisms controlling gene imprinting may contribute to barriers to interspecies chimerism. Overall, our conceptual framework opens new avenues to investigate the mechanistic basis of developmental processes and evolutionary divergence across myriad quantitative traits in any multicellular organism.
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Affiliation(s)
| | - Toshiya Nishimura
- Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
- WPI Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Osaka, 565-0871, Japan (current address for T.N.)
- Division of Stem Cell and Organoid Medicine, Department of Genome Biology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Kyomi J. Igarashi
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Chihiro Funamoto
- Division of Stem Cell and Organoid Medicine, Department of Genome Biology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Hiromitsu Nakauchi
- Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
- Division of Stem Cell Therapy, Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
| | - Hunter B. Fraser
- Department of Biology, Stanford University, Stanford, CA 94305, USA
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D’Occhio MJ, Campanile G, Baruselli PS, Porto Neto LR, Hayes BJ, Snr AC, Fortes MRS. Pleomorphic adenoma gene1 in reproduction and implication for embryonic survival in cattle: a review. J Anim Sci 2024; 102:skae103. [PMID: 38586898 PMCID: PMC11056886 DOI: 10.1093/jas/skae103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 04/05/2024] [Indexed: 04/09/2024] Open
Abstract
The pleomorphic adenoma gene1 (PLAG1) encodes a DNA-binding, C2H2 zinc-finger protein which acts as a transcription factor that regulates the expression of diverse genes across different organs and tissues; hence, the name pleomorphic. Rearrangements of the PLAG1 gene, and/or overexpression, are associated with benign tumors and cancers in a variety of tissues. This is best described for pleomorphic adenoma of the salivary glands in humans. The most notable expression of PLAG1 occurs during embryonic and fetal development, with lesser expression after birth. Evidence has accumulated of a role for PLAG1 protein in normal early embryonic development and placentation in mammals. PLAG1 protein influences the expression of the ike growth factor 2 (IGF2) gene and production of IGF2 protein. IGF2 is an important mitogen in ovarian follicles/oocytes, embryos, and fetuses. The PLAG1-IGF2 axis, therefore, provides one pathway whereby PLAG1 protein can influence embryonic survival and pregnancy. PLAG1 also influences over 1,000 other genes in embryos including those associated with ribosomal assembly and proteins. Brahman (Bos indicus) heifers homozygous for the PLAG1 variant, rs109815800 (G > T), show greater fertility than contemporary heifers with either one, or no copy, of the variant. Greater fertility in heifers homozygous for rs109815800 could be the result of early puberty and/or greater embryonic survival. The present review first looks at the broader roles of the PLAG1 gene and PLAG1 protein and then focuses on the emerging role of PLAG1/PLAG1 in embryonic development and pregnancy. A deeper understanding of factors which influence embryonic development is required for the next transformational increase in embryonic survival and successful pregnancy for both in vivo and in vitro derived embryos in cattle.
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Affiliation(s)
- Michael J D’Occhio
- School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, NSW, Australia
| | - Giuseppe Campanile
- Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Naples, Italy
| | - Pietro S Baruselli
- Faculty of Veterinary Medicine and Animal Science, Department of Animal Reproduction, University of Sao Paulo, Sao Paulo, Brazil
| | | | - Ben J Hayes
- Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, Brisbane, QLD, Australia
| | - Alf Collins Snr
- CBV Brahman, Marlborough, Central Queensland, QLD, Australia
| | - Marina R S Fortes
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
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MacPhillamy C, Chen T, Hiendleder S, Williams JL, Alinejad-Rokny H, Low WY. DNA methylation analysis to differentiate reference, breed, and parent-of-origin effects in the bovine pangenome era. Gigascience 2024; 13:giae061. [PMID: 39435573 PMCID: PMC11484048 DOI: 10.1093/gigascience/giae061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 03/19/2024] [Accepted: 07/25/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND Most DNA methylation studies have used a single reference genome with little attention paid to the bias introduced due to the reference chosen. Reference genome artifacts and genetic variation, including single nucleotide polymorphisms (SNPs) and structural variants (SVs), can lead to differences in methylation sites (CpGs) between individuals of the same species. We analyzed whole-genome bisulfite sequencing data from the fetal liver of Angus (Bos taurus taurus), Brahman (Bos taurus indicus), and reciprocally crossed samples. Using reference genomes for each breed from the Bovine Pangenome Consortium, we investigated the influence of reference genome choice on the breed and parent-of-origin effects in methylome analyses. RESULTS Our findings revealed that ∼75% of CpG sites were shared between Angus and Brahman, ∼5% were breed specific, and ∼20% were unresolved. We demonstrated up to ∼2% quantification bias in global methylation when an incorrect reference genome was used. Furthermore, we found that SNPs impacted CpGs 13 times more than other autosomal sites (P < $5 \times {10}^{ - 324}$) and SVs contained 1.18 times (P < $5 \times {10}^{ - 324}$) more CpGs than non-SVs. We found a poor overlap between differentially methylated regions (DMRs) and differentially expressed genes (DEGs) and suggest that DMRs may be impacting enhancers that target these DEGs. DMRs overlapped with imprinted genes, of which 1, DGAT1, which is important for fat metabolism and weight gain, was found in the breed-specific and sire-of-origin comparisons. CONCLUSIONS This work demonstrates the need to consider reference genome effects to explore genetic and epigenetic differences accurately and identify DMRs involved in controlling certain genes.
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Affiliation(s)
- Callum MacPhillamy
- The Davies Research Centre, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy SA 5371, Australia
| | - Tong Chen
- The Davies Research Centre, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy SA 5371, Australia
| | - Stefan Hiendleder
- The Davies Research Centre, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy SA 5371, Australia
- Robinson Research Institute,, The University of Adelaide, North Adelaide SA 5006, Australia
| | - John L Williams
- The Davies Research Centre, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy SA 5371, Australia
- Department of Animal Science, Food and Nutrition, Università Cattolica del Sacro Cuore, 29122 Piacenza, Italy
| | - Hamid Alinejad-Rokny
- BioMedical Machine Learning Lab, The Graduate School of Biomedical Engineering, Univeristy of New South Wales, Sydney, NSW 2052, Australia
| | - Wai Yee Low
- The Davies Research Centre, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy SA 5371, Australia
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Weinberg-Shukron A, Youngson NA, Ferguson-Smith AC, Edwards CA. Epigenetic control and genomic imprinting dynamics of the Dlk1-Dio3 domain. Front Cell Dev Biol 2023; 11:1328806. [PMID: 38155837 PMCID: PMC10754522 DOI: 10.3389/fcell.2023.1328806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 11/27/2023] [Indexed: 12/30/2023] Open
Abstract
Genomic imprinting is an epigenetic process whereby genes are monoallelically expressed in a parent-of-origin-specific manner. Imprinted genes are frequently found clustered in the genome, likely illustrating their need for both shared regulatory control and functional inter-dependence. The Dlk1-Dio3 domain is one of the largest imprinted clusters. Genes in this region are involved in development, behavior, and postnatal metabolism: failure to correctly regulate the domain leads to Kagami-Ogata or Temple syndromes in humans. The region contains many of the hallmarks of other imprinted domains, such as long non-coding RNAs and parental origin-specific CTCF binding. Recent studies have shown that the Dlk1-Dio3 domain is exquisitely regulated via a bipartite imprinting control region (ICR) which functions differently on the two parental chromosomes to establish monoallelic expression. Furthermore, the Dlk1 gene displays a selective absence of imprinting in the neurogenic niche, illustrating the need for precise dosage modulation of this domain in different tissues. Here, we discuss the following: how differential epigenetic marks laid down in the gametes cause a cascade of events that leads to imprinting in the region, how this mechanism is selectively switched off in the neurogenic niche, and why studying this imprinted region has added a layer of sophistication to how we think about the hierarchical epigenetic control of genome function.
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Affiliation(s)
| | - Neil A. Youngson
- School of BioSciences, The University of Melbourne, Parkville, VIC, Australia
| | | | - Carol A. Edwards
- Department of Genetics, University of Cambridge, Cambridge, United Kingdom
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Duo T, Liu X, Mo D, Bian Y, Cai S, Wang M, Li R, Zhu Q, Tong X, Liang Z, Jiang W, Chen S, Chen Y, He Z. Single-base editing in IGF2 improves meat production and intramuscular fat deposition in Liang Guang Small Spotted pigs. J Anim Sci Biotechnol 2023; 14:141. [PMID: 37919760 PMCID: PMC10621156 DOI: 10.1186/s40104-023-00930-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 08/06/2023] [Indexed: 11/04/2023] Open
Abstract
BACKGROUND Chinese indigenous pigs are popular with consumers for their juiciness, flavour and meat quality, but they have lower meat production. Insulin-like growth factor 2 (IGF2) is a maternally imprinted growth factor that promotes skeletal muscle growth by regulating cell proliferation and differentiation. A single nucleotide polymorphism (SNP) within intron 3 of porcine IGF2 disrupts a binding site for the repressor, zinc finger BED-type containing 6 (ZBED6), leading to up-regulation of IGF2 and causing major effects on muscle growth, heart size, and backfat thickness. This favorable mutation is common in Western commercial pig populations, but absent in most Chinese indigenous pig breeds. To improve meat production of Chinese indigenous pigs, we used cytosine base editor 3 (CBE3) to introduce IGF2-intron3-C3071T mutation into porcine embryonic fibroblasts (PEFs) isolated from a male Liang Guang Small Spotted pig (LGSS), and single-cell clones harboring the desired mutation were selected for somatic cell nuclear transfer (SCNT) to generate the founder line of IGF2T/T pigs. RESULTS We found the heterozygous progeny IGF2C/T pigs exhibited enhanced expression of IGF2, increased lean meat by 18%-36%, enlarged loin muscle area by 3%-17%, improved intramuscular fat (IMF) content by 18%-39%, marbling score by 0.75-1, meat color score by 0.53-1.25, and reduced backfat thickness by 5%-16%. The enhanced accumulation of intramuscular fat in IGF2C/T pigs was identified to be regulated by the PI3K-AKT/AMPK pathway, which activated SREBP1 to promote adipogenesis. CONCLUSIONS We demonstrated the introduction of IGF2-intron3-C3071T in Chinese LGSS can improve both meat production and quality, and first identified the regulation of IMF deposition by IGF2 through SREBP1 via the PI3K-AKT/AMPK signaling pathways. Our study provides a further understanding of the biological functions of IGF2 and an example for improving porcine economic traits through precise base editing.
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Affiliation(s)
- Tianqi Duo
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China
| | - Xiaohong Liu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China
| | - Delin Mo
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China
| | - Yu Bian
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Shufang Cai
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China
- Hunan Provincial Key Laboratory for Genetic Improvement of Domestic Animal, College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, China
| | - Min Wang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China
| | - Ruiqiang Li
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China
| | - Qi Zhu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China
| | - Xian Tong
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China
| | - Ziyun Liang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China
| | - Weilun Jiang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China
| | - Shiyi Chen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China
| | - Yaosheng Chen
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China.
| | - Zuyong He
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China.
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Abstract
Nutrient intake is obligatory for animal growth and development, but nutrients alone are not sufficient. Indeed, insulin and homologous hormones are required for normal growth even in the presence of nutrients. These hormones communicate nutrient status between organs, allowing animals to coordinate growth and metabolism with nutrient supply. Insulin and related hormones, such as insulin-like growth factors and insulin-like peptides, play important roles in development and metabolism, with defects in insulin production and signaling leading to hyperglycemia and diabetes. Here, we describe the insulin hormone family and the signal transduction pathways activated by these hormones. We highlight the roles of insulin signaling in coordinating maternal and fetal metabolism and growth during pregnancy, and we describe how secretion of insulin is regulated at different life stages. Additionally, we discuss the roles of insulin signaling in cell growth, stem cell proliferation and cell differentiation. We provide examples of the role of insulin in development across multiple model organisms: Caenorhabditis elegans, Drosophila, zebrafish, mouse and human.
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Affiliation(s)
- Miyuki Suzawa
- Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
| | - Michelle L. Bland
- Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
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Alberini CM. IGF2 in memory, neurodevelopmental disorders, and neurodegenerative diseases. Trends Neurosci 2023; 46:488-502. [PMID: 37031050 PMCID: PMC10192130 DOI: 10.1016/j.tins.2023.03.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 01/27/2023] [Accepted: 03/12/2023] [Indexed: 04/08/2023]
Abstract
Insulin-like growth factor 2 (IGF2) emerged as a critical mechanism of synaptic plasticity and learning and memory. Deficits in IGF2 in the brain, serum, or cerebrospinal fluid (CSF) are associated with brain diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Increasing IGF2 levels enhances memory in healthy animals and reverses numerous symptoms in laboratory models of aging, neurodevelopmental disorders, and neurodegenerative diseases. These effects occur via the IGF2 receptor (IGF2R) - a receptor that is highly expressed in neurons and regulates protein trafficking, synthesis, and degradation. Here, I summarize the current knowledge regarding IGF2 expression and functions in the brain, particularly in memory, and propose a novel conceptual model for IGF2/IGF2R mechanisms of action in brain health and diseases.
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Head ST, Leslie EJ, Cutler DJ, Epstein MP. POIROT: a powerful test for parent-of-origin effects in unrelated samples leveraging multiple phenotypes. Bioinformatics 2023; 39:btad199. [PMID: 37067493 PMCID: PMC10148680 DOI: 10.1093/bioinformatics/btad199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 04/03/2023] [Accepted: 04/06/2023] [Indexed: 04/18/2023] Open
Abstract
MOTIVATION There is widespread interest in identifying genetic variants that exhibit parent-of-origin effects (POEs) wherein the effect of an allele on phenotype expression depends on its parental origin. POEs can arise from different phenomena including genomic imprinting and have been documented for many complex traits. Traditional tests for POEs require family data to determine parental origins of transmitted alleles. As most genome-wide association studies (GWAS) sample unrelated individuals (where allelic parental origin is unknown), the study of POEs in such datasets requires sophisticated statistical methods that exploit genetic patterns we anticipate observing when POEs exist. We propose a method to improve discovery of POE variants in large-scale GWAS samples that leverages potential pleiotropy among multiple correlated traits often collected in such studies. Our method compares the phenotypic covariance matrix of heterozygotes to homozygotes based on a Robust Omnibus Test. We refer to our method as the Parent of Origin Inference using Robust Omnibus Test (POIROT) of multiple quantitative traits. RESULTS Through simulation studies, we compared POIROT to a competing univariate variance-based method which considers separate analysis of each phenotype. We observed POIROT to be well-calibrated with improved power to detect POEs compared to univariate methods. POIROT is robust to non-normality of phenotypes and can adjust for population stratification and other confounders. Finally, we applied POIROT to GWAS data from the UK Biobank using BMI and two cholesterol phenotypes. We identified 338 genome-wide significant loci for follow-up investigation. AVAILABILITY AND IMPLEMENTATION The code for this method is available at https://github.com/staylorhead/POIROT-POE.
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Affiliation(s)
- S Taylor Head
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, United States
| | - Elizabeth J Leslie
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - David J Cutler
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Michael P Epstein
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, United States
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10
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Richard Albert J, Kobayashi T, Inoue A, Monteagudo-Sánchez A, Kumamoto S, Takashima T, Miura A, Oikawa M, Miura F, Takada S, Hirabayashi M, Korthauer K, Kurimoto K, Greenberg MVC, Lorincz M, Kobayashi H. Conservation and divergence of canonical and non-canonical imprinting in murids. Genome Biol 2023; 24:48. [PMID: 36918927 PMCID: PMC10012579 DOI: 10.1186/s13059-023-02869-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 02/09/2023] [Indexed: 03/15/2023] Open
Abstract
BACKGROUND Genomic imprinting affects gene expression in a parent-of-origin manner and has a profound impact on complex traits including growth and behavior. While the rat is widely used to model human pathophysiology, few imprinted genes have been identified in this murid. To systematically identify imprinted genes and genomic imprints in the rat, we use low input methods for genome-wide analyses of gene expression and DNA methylation to profile embryonic and extraembryonic tissues at allele-specific resolution. RESULTS We identify 14 and 26 imprinted genes in these tissues, respectively, with 10 of these genes imprinted in both tissues. Comparative analyses with mouse reveal that orthologous imprinted gene expression and associated canonical DNA methylation imprints are conserved in the embryo proper of the Muridae family. However, only 3 paternally expressed imprinted genes are conserved in the extraembryonic tissue of murids, all of which are associated with non-canonical H3K27me3 imprints. The discovery of 8 novel non-canonical imprinted genes unique to the rat is consistent with more rapid evolution of extraembryonic imprinting. Meta-analysis of novel imprinted genes reveals multiple mechanisms by which species-specific imprinted expression may be established, including H3K27me3 deposition in the oocyte, the appearance of ZFP57 binding motifs, and the insertion of endogenous retroviral promoters. CONCLUSIONS In summary, we provide an expanded list of imprinted loci in the rat, reveal the extent of conservation of imprinted gene expression, and identify potential mechanisms responsible for the evolution of species-specific imprinting.
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Affiliation(s)
| | - Toshihiro Kobayashi
- Division of Mammalian Embryology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Azusa Inoue
- YCI Laboratory for Metabolic Epigenetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | | | - Soichiro Kumamoto
- NODAI Genome Research Center, Tokyo University of Agriculture, Tokyo, Japan
| | | | - Asuka Miura
- NODAI Genome Research Center, Tokyo University of Agriculture, Tokyo, Japan
| | - Mami Oikawa
- Division of Mammalian Embryology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Fumihito Miura
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Shuji Takada
- Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Masumi Hirabayashi
- Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Japan
| | - Keegan Korthauer
- Department of Statistics, University of British Columbia, Vancouver, Canada
- BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Kazuki Kurimoto
- Department of Embryology, Nara Medical University, Nara, Japan
| | | | - Matthew Lorincz
- Department of Medical Genetics, University of British Columbia, Vancouver, Canada
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11
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Lozano-Ureña A, Lázaro-Carot L, Jiménez-Villalba E, Montalbán-Loro R, Mateos-White I, Duart-Abadía P, Martínez-Gurrea I, Nakayama KI, Fariñas I, Kirstein M, Gil-Sanz C, Ferrón SR. IGF2 interacts with the imprinted gene Cdkn1c to promote terminal differentiation of neural stem cells. Development 2023; 150:dev200563. [PMID: 36633189 PMCID: PMC9903205 DOI: 10.1242/dev.200563] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 11/23/2022] [Indexed: 01/13/2023]
Abstract
Adult neurogenesis is supported by multipotent neural stem cells (NSCs) with unique properties and growth requirements. Adult NSCs constitute a reversibly quiescent cell population that can be activated by extracellular signals from the microenvironment in which they reside in vivo. Although genomic imprinting plays a role in adult neurogenesis through dose regulation of some relevant signals, the roles of many imprinted genes in the process remain elusive. Insulin-like growth factor 2 (IGF2) is encoded by an imprinted gene that contributes to NSC maintenance in the adult subventricular zone through a biallelic expression in only the vascular compartment. We show here that IGF2 additionally promotes terminal differentiation of NSCs into astrocytes, neurons and oligodendrocytes by inducing the expression of the maternally expressed gene cyclin-dependent kinase inhibitor 1c (Cdkn1c), encoding the cell cycle inhibitor p57. Using intraventricular infusion of recombinant IGF2 in a conditional mutant strain with Cdkn1c-deficient NSCs, we confirm that p57 partially mediates the differentiation effects of IGF2 in NSCs and that this occurs independently of its role in cell-cycle progression, balancing the relationship between astrogliogenesis, neurogenesis and oligodendrogenesis.
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Affiliation(s)
- Anna Lozano-Ureña
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia 46100, Spain
- Departamento de Biología Celular, Universidad de Valencia, Valencia 46100, Spain
| | - Laura Lázaro-Carot
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia 46100, Spain
- Departamento de Biología Celular, Universidad de Valencia, Valencia 46100, Spain
| | - Esteban Jiménez-Villalba
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia 46100, Spain
- Departamento de Biología Celular, Universidad de Valencia, Valencia 46100, Spain
| | - Raquel Montalbán-Loro
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia 46100, Spain
- Departamento de Biología Celular, Universidad de Valencia, Valencia 46100, Spain
| | - Isabel Mateos-White
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia 46100, Spain
- Departamento de Biología Celular, Universidad de Valencia, Valencia 46100, Spain
| | - Pere Duart-Abadía
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia 46100, Spain
- Departamento de Biología Celular, Universidad de Valencia, Valencia 46100, Spain
| | - Irene Martínez-Gurrea
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia 46100, Spain
- Departamento de Biología Celular, Universidad de Valencia, Valencia 46100, Spain
| | - Keiichi I. Nakayama
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 819-0395, Japan
| | - Isabel Fariñas
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia 46100, Spain
- Departamento de Biología Celular, Universidad de Valencia, Valencia 46100, Spain
| | - Martina Kirstein
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia 46100, Spain
- Departamento de Biología Celular, Universidad de Valencia, Valencia 46100, Spain
| | - Cristina Gil-Sanz
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia 46100, Spain
- Departamento de Biología Celular, Universidad de Valencia, Valencia 46100, Spain
| | - Sacri R. Ferrón
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Universidad de Valencia, Valencia 46100, Spain
- Departamento de Biología Celular, Universidad de Valencia, Valencia 46100, Spain
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12
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Sánchez-Soriano C, Pearson ER, Reynolds RM. Associations between parental type 2 diabetes risk and offspring birthweight and placental weight: a survival analysis using the Walker cohort. Diabetologia 2022; 65:2084-2097. [PMID: 35951032 PMCID: PMC9630220 DOI: 10.1007/s00125-022-05776-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 06/22/2022] [Indexed: 01/11/2023]
Abstract
AIMS/HYPOTHESIS Low birthweight (BW) is associated with the development of type 2 diabetes. Genome-wide analyses have identified a strong genetic component to this association, with many BW-associated loci also involved in glucose metabolism. We hypothesised that offspring BW and placental weight (PW) are correlated with parental type 2 diabetes risk, reflecting the inheritance of diabetes risk alleles that also influence fetal growth. METHODS The Walker cohort, a collection of birth records from Dundee, Scotland, from the 1950s and the 1960s was used to test this hypothesis by linking BW and PW measurements to parental health outcomes. Using data from SCI-Diabetes and the national death registry, we obtained health records for over 20,000 Walker parents. We performed Fine-Gray survival analyses of parental type 2 diabetes risk with competing risk of death, and Cox regression analyses of risk of death, independently in the maternal and paternal datasets, modelled by offspring BW and PW. RESULTS We found significant associations between increased paternal type 2 diabetes risk and reduced offspring BW (subdistribution hazard ratio [SHR] 0.92 [95% CI 0.87, 0.98]) and PW (SHR 0.87 [95% CI 0.81, 0.94]). The association of maternal type 2 diabetes risk with offspring BW or PW was not significant. Lower offspring BW was also associated with increased risk of death in both mothers (HR 0.91 [95% CI 0.89, 0.94]) and fathers (HR 0.95 [95% CI 0.92, 0.98]), and higher offspring PW was associated with increased maternal mortality risk (HR 1.08 [95% CI 1.04, 1.13]) when adjusted for BW. CONCLUSIONS/INTERPRETATION We identified associations between offspring BW and reduced paternal type 2 diabetes risk, most likely resulting from the independent effects of common type 2 diabetes susceptibility alleles on fetal growth, as described by the fetal insulin hypothesis. Moreover, we identified novel associations between offspring PW and reduced paternal type 2 diabetes risk, a relationship that might also be caused by the inheritance of diabetes predisposition variants. We found differing associations between offspring BW and PW and parental risk of death. These results provide novel epidemiological support for the use of offspring BW and PW as predictors for future risk of type 2 diabetes and death in mothers and fathers.
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Affiliation(s)
- Carlos Sánchez-Soriano
- Centre for Cardiovascular Science, Deanery of Molecular, Genetic and Population Health Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Ewan R Pearson
- Division of Population Health and Genomics, Ninewells Hospital and School of Medicine, University of Dundee, Dundee, UK
| | - Rebecca M Reynolds
- Centre for Cardiovascular Science, Deanery of Molecular, Genetic and Population Health Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
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13
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Bhadsavle SS, Golding MC. Paternal epigenetic influences on placental health and their impacts on offspring development and disease. Front Genet 2022; 13:1068408. [PMID: 36468017 PMCID: PMC9716072 DOI: 10.3389/fgene.2022.1068408] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 11/04/2022] [Indexed: 07/25/2023] Open
Abstract
Our efforts to understand the developmental origins of birth defects and disease have primarily focused on maternal exposures and intrauterine stressors. Recently, research into non-genomic mechanisms of inheritance has led to the recognition that epigenetic factors carried in sperm also significantly impact the health of future generations. However, although researchers have described a range of potential epigenetic signals transmitted through sperm, we have yet to obtain a mechanistic understanding of how these paternally-inherited factors influence offspring development and modify life-long health. In this endeavor, the emerging influence of the paternal epigenetic program on placental development, patterning, and function may help explain how a diverse range of male exposures induce comparable intergenerational effects on offspring health. During pregnancy, the placenta serves as the dynamic interface between mother and fetus, regulating nutrient, oxygen, and waste exchange and coordinating fetal growth and maturation. Studies examining intrauterine maternal stressors routinely describe alterations in placental growth, histological organization, and glycogen content, which correlate with well-described influences on infant health and adult onset of disease. Significantly, the emergence of similar phenotypes in models examining preconception male exposures indicates that paternal stressors transmit an epigenetic memory to their offspring that also negatively impacts placental function. Like maternal models, paternally programmed placental dysfunction exerts life-long consequences on offspring health, particularly metabolic function. Here, focusing primarily on rodent models, we review the literature and discuss the influences of preconception male health and exposure history on placental growth and patterning. We emphasize the emergence of common placental phenotypes shared between models examining preconception male and intrauterine stressors but note that the direction of change frequently differs between maternal and paternal exposures. We posit that alterations in placental growth, histological organization, and glycogen content broadly serve as reliable markers of altered paternal developmental programming, predicting the emergence of structural and metabolic defects in the offspring. Finally, we suggest the existence of an unrecognized developmental axis between the male germline and the extraembryonic lineages that may have evolved to enhance fetal adaptation.
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Affiliation(s)
| | - Michael C. Golding
- Department of Veterinary Physiology and Pharmacology, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, United States
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14
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Lin S, Yi S, Qiu P. Comprehensive analysis of TCGA data reveals correlation between DNA methylation and alternative splicing. BMC Genomics 2022; 23:758. [PMID: 36401166 PMCID: PMC9675104 DOI: 10.1186/s12864-022-08992-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 11/05/2022] [Indexed: 11/21/2022] Open
Abstract
The effect of DNA methylation on the regulation of gene expression has been extensively discussed in the literature. However, the potential association between DNA methylation and alternative splicing is not understood well. In this study, we integrated multiple omics data types from The Cancer Genome Atlas (TCGA) and systematically examined the relationship between DNA methylation and alternative splicing. Using the methylation data and exon expression data, we identified many CpG sites significantly associated with exon expression in various types of cancers. We further observed that the direction and strength of significant CpG-exon correlation tended to be consistent across different cancer contexts, indicating that some CpG-exon correlation patterns reflect fundamental biological mechanisms that transcend tissue- and cancer- types. We also discovered that CpG sites correlated with exon expressions were more likely to be associated with patient survival outcomes compared to CpG sites that did not correlate with exon expressions. Furthermore, we found that CpG sites were more strongly correlated with exon expression than expression of isoforms harboring the corresponding exons. This observation suggests that a major effect of CpG methylation on alternative splicing may be related to the inclusion or exclusion of exons, which subsequently impacts the relative usage of various isoforms. Overall, our study revealed correlation patterns between DNA methylation and alternative splicing, which provides new insights into the role of methylation in the transcriptional process.
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Affiliation(s)
- Shuting Lin
- grid.213917.f0000 0001 2097 4943School of Biological Sciences, Georgia Institute of Technology, Atlanta, USA
| | - Soojin Yi
- grid.133342.40000 0004 1936 9676Ecology, Evolution, Marine Biology, University of California, Santa Barbara, Santa Barbara, USA
| | - Peng Qiu
- grid.213917.f0000 0001 2097 4943Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, USA
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15
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Anam AK, Cooke KM, Dratver MB, O'Bryan JV, Perley LE, Guller SM, Hwang JJ, Taylor HS, Goedeke L, Kliman HJ, Vatner DF, Flannery CA. Insulin increases placental triglyceride as a potential mechanism for fetal adiposity in maternal obesity. Mol Metab 2022; 64:101574. [PMID: 35970449 PMCID: PMC9440306 DOI: 10.1016/j.molmet.2022.101574] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/27/2022] [Accepted: 08/08/2022] [Indexed: 01/07/2023] Open
Abstract
OBJECTIVE Maternal obesity increases the incidence of excess adiposity in newborns, resulting in lifelong diabetes risk. Elevated intrauterine fetal adiposity has been attributed to maternal hyperglycemia; however, this hypothesis does not account for the increased adiposity seen in newborns of mothers with obesity who have euglycemia. We aimed to explore the placental response to maternal hyperinsulinemia and the effect of insulin-like growth factor 2 (IGF-2) in promoting fetal adiposity by increasing storage and availability of nutrients to the fetus. METHODS We used placental villous explants and isolated trophoblasts from normal weight and obese women to assess the effect of insulin and IGF-2 on triglyceride content and insulin receptor signaling. Stable isotope tracer methods were used ex vivo to determine effect of hormone treatment on de novo lipogenesis (DNL), fatty acid uptake, fatty acid oxidation, and esterification in the placenta. RESULTS Here we show that placentae from euglycemic women with normal weight and obesity both have abundant insulin receptor. Placental depth and triglyceride were greater in women with obesity compared with normal weight women. In syncytialized placental trophoblasts and villous explants, insulin and IGF-2 activate insulin receptor, induce expression of lipogenic transcription factor SREBP-1 (sterol regulatory element-binding protein 1), and stimulate triglyceride accumulation. We demonstrate elevated triglyceride is attributable to increased esterification of fatty acids, without contribution from DNL and without an acceleration of fatty acid uptake. CONCLUSIONS Our work reveals that obesity-driven aberrations in maternal metabolism, such as hyperinsulinemia, alter placental metabolism in euglycemic conditions, and may explain the higher prevalence of excess adiposity in the newborns of obese women.
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Affiliation(s)
- Anika K Anam
- Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Katherine M Cooke
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Milana Bochkur Dratver
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Jane V O'Bryan
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Lauren E Perley
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Seth M Guller
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Janice J Hwang
- Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Hugh S Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Leigh Goedeke
- Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Harvey J Kliman
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Daniel F Vatner
- Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Clare A Flannery
- Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
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16
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The Insulin-like Growth Factor System and Colorectal Cancer. LIFE (BASEL, SWITZERLAND) 2022; 12:life12081274. [PMID: 36013453 PMCID: PMC9410426 DOI: 10.3390/life12081274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 11/29/2022]
Abstract
Insulin-like growth factors (IGFs) are peptides which exert mitogenic, endocrine and cytokine activities. Together with their receptors, binding proteins and associated molecules, they participate in numerous pathophysiological processes, including cancer development. Colorectal cancer (CRC) is a disease with high incidence and mortality rates worldwide, whose etiology usually represents a combination of the environmental and genetic factors. IGFs are most often increased in CRC, enabling excessive autocrine/paracrine stimulation of the cell growth. Overexpression or increased activation/accessibility of IGF receptors is a coinciding step which transmits IGF-related signals. A number of molecules and biochemical mechanisms exert modulatory effects shaping the final outcome of the IGF-stimulated processes, frequently leading to neoplastic transformation in the case of irreparable disbalance. The IGF system and related molecules and pathways which participate in the development of CRC are the focus of this review.
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17
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Hou X, Wang Z, Shi L, Wang L, Zhao F, Liu X, Gao H, Shi L, Yan H, Wang L, Zhang L. Identification of imprinted genes in the skeletal muscle of newborn piglets by high-throughput sequencing. Anim Genet 2022; 53:479-486. [PMID: 35481679 DOI: 10.1111/age.13212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 04/01/2022] [Accepted: 04/13/2022] [Indexed: 11/28/2022]
Abstract
Imprinted genes - exhibiting parent-specific transcription - play essential roles in the process of mammalian development and growth. Skeletal muscle growth is crucial for meat production. To further understand the role of imprinted genes during the porcine skeletal muscle growth, DNA-seq and RNA-seq were used to explore the characteristics of imprinted genes from porcine reciprocal crosses. A total of 584 545 single-nucleotide variations were discovered in the DNA-seq data of F0 parents, heterozygous in two pig breeds (Yorkshire and Min pigs) but homozygous in each breed. These single-nucleotide variations were used to determine the allelic-specific expression in F1 individuals. Finally, eight paternal expression sites and three maternal expression sites were detected, whereas two paternally expressed imprinted genes (NDN and IGF2) and one maternally expressed imprinted gene (H1-3) were validated by Sanger sequencing. DNA methylation regulates the expression of imprinted genes, and all of the identified imprinted genes in this study were predicted to possess CpG islands. PBX1 and YY1 binding motifs were discovered in the promoter regions of all three imprinted genes, which were candidate elements regulating the transcription of imprinted genes. For these identified imprinted genes, IGF2 and NDN promoted muscle growth whereas H1-3 inhibited cell proliferation, corroborating the 'parental conflict' theory that paternally expressed imprinted genes assisted descendants' growth whereas maternally expressed imprinted genes inhibited it. This study discovered porcine imprinted genes in skeletal muscle and was the first to reveal that H1-3 was expressed by the maternal allele to our knowledge. Our findings provided valuable resources for the potential utilization of imprinted genes in pig breeding.
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Affiliation(s)
- Xinhua Hou
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Zishuai Wang
- Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China
| | - Liangyu Shi
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China.,School of Animal Science and Nutritional Engineering, Wuhan Polytechnic University, Wuhan, China
| | - Ligang Wang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Fuping Zhao
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Xin Liu
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Hongmei Gao
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Lijun Shi
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Hua Yan
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Lixian Wang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Longchao Zhang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, China
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18
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Bencivenga D, Stampone E, Vastante A, Barahmeh M, Della Ragione F, Borriello A. An Unanticipated Modulation of Cyclin-Dependent Kinase Inhibitors: The Role of Long Non-Coding RNAs. Cells 2022; 11:cells11081346. [PMID: 35456025 PMCID: PMC9028986 DOI: 10.3390/cells11081346] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 12/13/2022] Open
Abstract
It is now definitively established that a large part of the human genome is transcribed. However, only a scarce percentage of the transcriptome (about 1.2%) consists of RNAs that are translated into proteins, while the large majority of transcripts include a variety of RNA families with different dimensions and functions. Within this heterogeneous RNA world, a significant fraction consists of sequences with a length of more than 200 bases that form the so-called long non-coding RNA family. The functions of long non-coding RNAs range from the regulation of gene transcription to the changes in DNA topology and nucleosome modification and structural organization, to paraspeckle formation and cellular organelles maturation. This review is focused on the role of long non-coding RNAs as regulators of cyclin-dependent kinase inhibitors’ (CDKIs) levels and activities. Cyclin-dependent kinases are enzymes necessary for the tuned progression of the cell division cycle. The control of their activity takes place at various levels. Among these, interaction with CDKIs is a vital mechanism. Through CDKI modulation, long non-coding RNAs implement control over cellular physiology and are associated with numerous pathologies. However, although there are robust data in the literature, the role of long non-coding RNAs in the modulation of CDKIs appears to still be underestimated, as well as their importance in cell proliferation control.
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19
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Brabazon DC, Callanan JJ, Nolan CM. Imprinting of canine IGF2 and H19. Anim Genet 2021; 53:108-118. [PMID: 34676575 DOI: 10.1111/age.13148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/08/2021] [Indexed: 11/29/2022]
Abstract
Genomic imprinting occurs in therian mammals and is a phenomenon whereby the two alleles of a gene are differentially expressed, based on the sex of the parent from whom the alleles were inherited. The allelic differences in expression are the consequence of different epigenetic modifications that are established in the sperm or oocyte during gametogenesis and transmitted at fertilization to offspring. A small minority of genes is regulated in this way but they have important biological functions, and aberrant regulation of imprinted genes contributes to disease aetiology in humans and other animals. The factors driving the evolution of imprinted genes are also of considerable interest, as these genes appear to forego the benefits of diploidy. To broaden the phylogenetic analysis of genomic imprinting, we began a study of imprinted genes in the domestic dog, Canis familiaris. In this report, we show that canine IGF2 and H19 are imprinted, with parent-of origin-dependent monoallelic expression patterns in neonatal umbilical cord. We identify a putative imprint control region associated with the genes, and provide evidence for differential methylation of this region in a somatic tissue (umbilical cord) and for its hypermethylation in the male germline. Canis familiaris is fast becoming a highly informative system for elucidating disease processes and evolution, and the study of imprinted genes in this species may help in understanding how these genes contribute to the generation of morphological and behavioral diversity.
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Affiliation(s)
- D C Brabazon
- University College Dublin School of Biology and Environmental Science, Belfield, Dublin 4, Ireland
| | - J J Callanan
- University College Dublin School of Veterinary Medicine, Belfield, Dublin 4, Ireland
| | - C M Nolan
- University College Dublin School of Biology and Environmental Science, Belfield, Dublin 4, Ireland
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20
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Li S, Wang W, Zhang D, Li W, Lund J, Kruse T, Mengel-From J, Christensen K, Tan Q. Differential regulation of the DNA methylome in adults born during the Great Chinese Famine in 1959-1961. Genomics 2021; 113:3907-3918. [PMID: 34600028 DOI: 10.1016/j.ygeno.2021.09.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 08/24/2021] [Accepted: 09/25/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND Extensive epidemiological studies have established the association between exposure to early-life adversity and health status and diseases in adults. Epigenetic regulation is considered as a key mediator for this phenomenon but analysis on humans is sparse. The Great Chinese Famine lasting from 1958 to 1961 is a natural string of disasters offering a precious opportunity for elucidating the underlying epigenetic mechanism of the long-term effect of early adversity. METHODS Using a high-throughput array platform for DNA methylome profiling, we conducted a case-control epigenome-wide association study on early-life exposure to Chinese famine in 79 adults born during 1959-1961 and compared to 105 unexposed subjects born 1963-1964. RESULTS The single CpG site analysis of whole epigenome revealed a predominant pattern of decreased DNA methylation levels associated with fetal exposure to famine. Four CpG sites were detected with p < 1e-06 (linked to EHMT1, CNR1, UBXN7 and ESM1 genes), 16 CpGs detected with 1e-06 < p < 1e-05 and 157 CpGs with 1e-05 < p < 1e-04, with a predominant pattern of hypomethylation. Functional annotation to genes and their enriched biological pathways mainly involved neurodevelopment, neuropsychological disorders and metabolism. Multiple sites analysis detected two top-rank differentially methylated regions harboring RNF39 on chromosome 6 and PTPRN2 on chromosome 7, both showing epigenetic association with stress-related conditions. CONCLUSION Early-life exposure to famine could mediate DNA methylation regulations that persist into adulthood with broad impacts in the activities of genes and biological pathways. Results from this study provide new clues to the epigenetic embedding of early-life adversity and its impacts on adult health.
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Affiliation(s)
- Shuxia Li
- Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark.
| | - Weijing Wang
- Qingdao University School of Public Health, Qingdao, China
| | - Dongfeng Zhang
- Qingdao University School of Public Health, Qingdao, China
| | - Weilong Li
- Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark; Population Research Unit, Faculty of Social Sciences, University of Helsinki, Finland.
| | - Jesper Lund
- Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark; Digital Health & Machine Learning Research Group, Hasso Plattner Institute for Digital Engineering, Potsdam, Germany.
| | - Torben Kruse
- Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
| | - Jonas Mengel-From
- Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark.
| | - Kaare Christensen
- Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark.
| | - Qihua Tan
- Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark; Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
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21
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Steane SE, Fielding AM, Kent NL, Andersen I, Browne DJ, Tejo EN, Gårdebjer EM, Kalisch-Smith JI, Sullivan MA, Moritz KM, Akison LK. Maternal choline supplementation in a rat model of periconceptional alcohol exposure: Impacts on the fetus and placenta. Alcohol Clin Exp Res 2021; 45:2130-2146. [PMID: 34342027 DOI: 10.1111/acer.14685] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 06/26/2021] [Accepted: 07/22/2021] [Indexed: 12/28/2022]
Abstract
BACKGROUND Maternal choline supplementation in rats can ameliorate specific neurological and behavioral abnormalities caused by alcohol exposure during pregnancy. We tested whether choline supplementation ameliorates fetal growth restriction and molecular changes in the placenta associated with periconceptional ethanol exposure (PCE) in the rat. METHODS Sprague Dawley dams were given either 12.5% ethanol (PCE) or 0% ethanol (Con) in a liquid diet from 4 days prior to 4 days after conception. At day 5 of pregnancy, dams were either placed on a standard chow (1.6 g choline/kg chow) or an intermediate chow (2.6 g choline/kg chow). On day 10 of pregnancy, a subset of the intermediate dams were placed on a chow further supplemented with choline (7.2 g choline/kg chow), resulting in 6 groups. Fetuses and placentas were collected on day 20 of pregnancy for analysis. RESULTS Choline supplementation resulted in increased fetal weight at late gestation, ameliorating the deficits due to PCE. This was most pronounced in litters on a standard chow during pregnancy. Choline also increased fetal liver weight and decreased fetal brain:liver ratio, independent of alcohol exposure. Placental weight was reduced as choline levels in the chow increased, particularly in female placentas. This resulted in a greater ratio of fetal:placental weight, suggesting increased placental efficiency. Global DNA methylation in the placenta was altered in a sex-specific manner by both PCE and choline. However, the increased glycogen deposition in female placentas, previously reported in this PCE model, was not prevented by choline supplementation. CONCLUSIONS Our results suggest that choline has the potential to ameliorate fetal growth restriction associated with PCE and improve placental efficiency following prenatal alcohol exposure. Our study highlights the importance of maternal nutrition in moderating the severity of adverse fetal and placental outcomes that may arise from prenatal alcohol exposure around the time of conception.
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Affiliation(s)
- Sarah E Steane
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Arree M Fielding
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Nykola L Kent
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Isabella Andersen
- Child Health Research Centre, The University of Queensland, South Brisbane, QLD, Australia
| | - Daniel J Browne
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Ellen N Tejo
- Mater Research, The University of Queensland, Woolloongabba, QLD, Australia
| | - Emelie M Gårdebjer
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | | | | | - Karen M Moritz
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Lisa K Akison
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia.,Child Health Research Centre, The University of Queensland, South Brisbane, QLD, Australia
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22
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Tang X, Zuo C, Fang P, Liu G, Qiu Y, Huang Y, Tang R. Targeting Glioblastoma Stem Cells: A Review on Biomarkers, Signal Pathways and Targeted Therapy. Front Oncol 2021; 11:701291. [PMID: 34307170 PMCID: PMC8297686 DOI: 10.3389/fonc.2021.701291] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 06/25/2021] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma (GBM) remains the most lethal and common primary brain tumor, even after treatment with multiple therapies, such as surgical resection, chemotherapy, and radiation. Although great advances in medical development and improvements in therapeutic methods of GBM have led to a certain extension of the median survival time of patients, prognosis remains poor. The primary cause of its dismal outcomes is the high rate of tumor recurrence, which is closely related to its resistance to standard therapies. During the last decade, glioblastoma stem cells (GSCs) have been successfully isolated from GBM, and it has been demonstrated that these cells are likely to play an indispensable role in the formation, maintenance, and recurrence of GBM tumors, indicating that GSCs are a crucial target for treatment. Herein, we summarize the current knowledge regarding GSCs, their related signaling pathways, resistance mechanisms, crosstalk linking mechanisms, and microenvironment or niche. Subsequently, we present a framework of targeted therapy for GSCs based on direct strategies, including blockade of the pathways necessary to overcome resistance or prevent their function, promotion of GSC differentiation, virotherapy, and indirect strategies, including targeting the perivascular, hypoxic, and immune niches of the GSCs. In summary, targeting GSCs provides a tremendous opportunity for revolutionary approaches to improve the prognosis and therapy of GBM, despite a variety of challenges.
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Affiliation(s)
- Xuejia Tang
- Department of Neurosurgery, University-Town Hospital of Chongqing Medical University, Chongqing, China.,Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Chenghai Zuo
- Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Pengchao Fang
- Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Guojing Liu
- Department of Neurosurgery, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Yongyi Qiu
- Department of Neurosurgery, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Huang
- Department of Neurosurgery, The Ninth People's Hospital of Chongqing, Chongqing, China
| | - Rongrui Tang
- Department of Neurosurgery, University-Town Hospital of Chongqing Medical University, Chongqing, China
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23
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Nadella KS, Berthon A, Almeida MQ, Levy I, Faucz FR, Stratakis CA. Insulin-like growth factor 2 (IGF2) expression in adrenocortical disease due to PRKAR1A mutations compared to other benign adrenal tumors. Endocrine 2021; 72:823-834. [PMID: 33420948 DOI: 10.1007/s12020-020-02583-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 12/01/2020] [Indexed: 01/19/2023]
Abstract
PURPOSE Insulin-like growth factor-II (IGF2), a key regulator of cell growth and development, is tightly regulated in its expression by epigenetic control that maintains its monoallelic expression in most tissues. Biallelic expression of IGF2 resulting from loss of imprinting (LOI) has been reported in adrenocortical tumors. In this study, we wanted to check whether adrenocortical lesions due to PRKAR1A mutations lead to increased IGF2 expression from LOI and compare these findings to those in other benign adrenal lesions. METHODS We compared the expression of IGF2 by RNA and protein studies in primary pigmented nodular adrenocortical disease (PPNAD) caused by PRKAR1A gene mutations to that in primary macronodular adrenocortical hyperplasia (PMAH) and cortisol-producing adenomas (CPA) that did not have any mutations in known genes. We also checked LOI in all lesions by DNA allelic studies and the expression of other components of IGF2 signaling at the RNA and protein level. RESULTS We identified cell clusters overexpressing IGF2 in PPNAD; although immunostaining was patchy, overall, by RNA and immunoblotting PPNAD expressed high IGF2 message and protein. However, this was not due to LOI, as there was no correlation between IGF2 expression and the presence of LOI. CONCLUSIONS Our data pointed to over-expression of IGF2 protein in PPNAD compared to other benign adrenocortical lesions, such as PMAH and CPA. However, there was no correlation of IGF2 mRNA levels with LOI of IGF2/H19. The discrepancy between mRNA and protein levels with regards to LOI points, perhaps, to different control of IGF2 gene expression in PPNAD.
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Affiliation(s)
- Kiran S Nadella
- Section on Genetics & Endocrinology (SEGEN), Intramural Research Program (IRP), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD, USA
| | - Annabel Berthon
- Section on Genetics & Endocrinology (SEGEN), Intramural Research Program (IRP), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD, USA
| | - Madson Q Almeida
- Section on Genetics & Endocrinology (SEGEN), Intramural Research Program (IRP), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD, USA
| | - Isaac Levy
- Section on Genetics & Endocrinology (SEGEN), Intramural Research Program (IRP), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD, USA
| | - Fabio R Faucz
- Section on Genetics & Endocrinology (SEGEN), Intramural Research Program (IRP), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD, USA.
| | - Constantine A Stratakis
- Section on Genetics & Endocrinology (SEGEN), Intramural Research Program (IRP), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD, USA
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24
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Lozano-Ureña A, Jiménez-Villalba E, Pinedo-Serrano A, Jordán-Pla A, Kirstein M, Ferrón SR. Aberrations of Genomic Imprinting in Glioblastoma Formation. Front Oncol 2021; 11:630482. [PMID: 33777782 PMCID: PMC7994891 DOI: 10.3389/fonc.2021.630482] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 02/15/2021] [Indexed: 12/21/2022] Open
Abstract
In human glioblastoma (GBM), the presence of a small population of cells with stem cell characteristics, the glioma stem cells (GSCs), has been described. These cells have GBM potential and are responsible for the origin of the tumors. However, whether GSCs originate from normal neural stem cells (NSCs) as a consequence of genetic and epigenetic changes and/or dedifferentiation from somatic cells remains to be investigated. Genomic imprinting is an epigenetic marking process that causes genes to be expressed depending on their parental origin. The dysregulation of the imprinting pattern or the loss of genomic imprinting (LOI) have been described in different tumors including GBM, being one of the earliest and most common events that occurs in human cancers. Here we have gathered the current knowledge of the role of imprinted genes in normal NSCs function and how the imprinting process is altered in human GBM. We also review the changes at particular imprinted loci that might be involved in the development of the tumor. Understanding the mechanistic similarities in the regulation of genomic imprinting between normal NSCs and GBM cells will be helpful to identify molecular players that might be involved in the development of human GBM.
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Affiliation(s)
- Anna Lozano-Ureña
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Valencia, Spain.,Departamento de Biología Celular, Universidad de Valencia, Valencia, Spain
| | | | | | | | - Martina Kirstein
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Valencia, Spain.,Departamento de Biología Celular, Universidad de Valencia, Valencia, Spain
| | - Sacri R Ferrón
- Instituto de Biotecnología y Biomedicina (BIOTECMED), Valencia, Spain.,Departamento de Biología Celular, Universidad de Valencia, Valencia, Spain
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25
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Hwa V, Fujimoto M, Zhu G, Gao W, Foley C, Kumbaji M, Rosenfeld RG. Genetic causes of growth hormone insensitivity beyond GHR. Rev Endocr Metab Disord 2021; 22:43-58. [PMID: 33029712 PMCID: PMC7979432 DOI: 10.1007/s11154-020-09603-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/01/2020] [Indexed: 12/13/2022]
Abstract
Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in severe post-natal growth failure as consequences of insulin-like growth factor I (IGF-I) deficiency. Over the years, recognition of other monogenic defects downstream of GHR has greatly expanded understanding of primary causes of GHI and growth retardation, with either IGF-I deficiency or IGF-I insensitivity as clinical outcomes. Mutations in IGF1 and signaling component STAT5B disrupt IGF-I production, while defects in IGFALS and PAPPA2, disrupt transport and release of circulating IGF-I, respectively, affecting bioavailability of the growth-promoting IGF-I. Defects in IGF1R, cognate cell-surface receptor for IGF-I, disrupt not only IGF-I actions, but actions of the related IGF-II peptides. The importance of IGF-II for normal developmental growth is emphasized with recent identification of defects in the maternally imprinted IGF2 gene. Current application of next-generation genomic sequencing has expedited the pace of identifying new molecular defects in known genes or in new genes, thereby expanding the spectrum of GH and IGF insensitivity. This review discusses insights gained and future directions from patient-based molecular and functional studies.
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Affiliation(s)
- Vivian Hwa
- Department of Pediatrics, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA.
| | - Masanobu Fujimoto
- Department of Pediatrics, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA
- Division of Pediatrics and Perinatology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago, 683-8504, Japan
| | - Gaohui Zhu
- Department of Pediatrics, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA
- Department of Endocrinology, Children's Hospital of Chongqing Medical University, Chongqing, 40014, China
| | - Wen Gao
- Department of Pediatrics, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA
| | - Corinne Foley
- Department of Pediatrics, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA
| | - Meenasri Kumbaji
- Department of Pediatrics, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA
| | - Ron G Rosenfeld
- Department of Pediatrics, Oregon Health & Science University, Portland, OR, 97239, USA.
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26
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Liao J, Zeng TB, Pierce N, Tran DA, Singh P, Mann JR, Szabó PE. Prenatal correction of IGF2 to rescue the growth phenotypes in mouse models of Beckwith-Wiedemann and Silver-Russell syndromes. Cell Rep 2021; 34:108729. [PMID: 33567274 PMCID: PMC7968144 DOI: 10.1016/j.celrep.2021.108729] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 12/02/2020] [Accepted: 01/15/2021] [Indexed: 12/19/2022] Open
Abstract
Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are imprinting disorders manifesting as aberrant fetal growth and severe postnatal-growth-related complications. Based on the insulator model, one-third of BWS cases and two-thirds of SRS cases are consistent with misexpression of insulin-like growth factor 2 (IGF2), an important facilitator of fetal growth. We propose that the IGF2-dependent BWS and SRS cases can be identified by prenatal diagnosis and can be prevented by prenatal intervention targeting IGF2. We test this hypothesis using our mouse models of IGF2-dependent BWS and SRS. We find that genetically normalizing IGF2 levels in a double rescue experiment corrects the fetal overgrowth phenotype in the BWS model and the growth retardation in the SRS model. In addition, we pharmacologically rescue the BWS growth phenotype by reducing IGF2 signaling during late gestation. This animal study encourages clinical investigations to target IGF2 for prenatal diagnosis and prenatal prevention in human BWS and SRS. Liao et al. use mouse models to test a prenatal approach for correcting growth anomalies in two imprinting diseases, BWS and SRS. They find that cases where the fetal growth factor IGF2 is misregulated can be diagnosed, and growth can be corrected by prenatally adjusting IGF2 or its signaling output.
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Affiliation(s)
- Ji Liao
- Center for Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Tie-Bo Zeng
- Center for Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Nicholas Pierce
- Center for Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
| | - Diana A Tran
- Division of Molecular and Cellular Biology, City of Hope Cancer Center, Duarte, CA 91010, USA; Irell and Manella Graduate School, City of Hope, Duarte, CA 91010, USA
| | - Purnima Singh
- Division of Molecular and Cellular Biology, City of Hope Cancer Center, Duarte, CA 91010, USA
| | - Jeffrey R Mann
- Division of Molecular and Cellular Biology, City of Hope Cancer Center, Duarte, CA 91010, USA
| | - Piroska E Szabó
- Center for Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.
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27
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The maturity in fetal pigs using a multi-fluid metabolomic approach. Sci Rep 2020; 10:19912. [PMID: 33199811 PMCID: PMC7670440 DOI: 10.1038/s41598-020-76709-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 10/28/2020] [Indexed: 12/27/2022] Open
Abstract
In mammalian species, the first days after birth are an important period for survival and the mortality rate is high before weaning. In pigs, perinatal deaths average 20% of the litter, with important economic and societal consequences. Maturity is one of the most important factors that influence piglet survival at birth. Maturity can be defined as the outcome of complex mechanisms of intra-uterine development and maturation during the last month of gestation. Here, we provide new insights into maturity obtained by studying the end of gestation at two different stages (3 weeks before term and close to term) in two breeds of pigs that strongly differ in terms of neonatal survival. We used metabolomics to characterize the phenotype, to identify biomarkers, and provide a comprehensive understanding of the metabolome of the fetuses in late gestation in three fluids (plasma, urine, and amniotic fluid). Our results show that the biological processes related to amino acid and carbohydrate metabolisms are critical for piglet maturity. We confirm the involvement of some previously described metabolites associated with delayed growth (e.g., proline and myo-inositol). Altogether, our study proposes new routes for improved characterization of piglet maturity at birth.
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28
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Lu S, Liang Q, Huang Y, Meng F, Liu J. Definition and review on a category of long non-coding RNA: Atherosclerosis-associated circulating lncRNA (ASCLncRNA). PeerJ 2020; 8:e10001. [PMID: 33240586 PMCID: PMC7666546 DOI: 10.7717/peerj.10001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 08/29/2020] [Indexed: 12/18/2022] Open
Abstract
Atherosclerosis (AS) is one of the most common cardiovascular system diseases which seriously affects public health in modern society. Finding potential biomarkers in the complicated pathological progression of AS is of great significance for the prevention and treatment of AS. Studies have shown that long noncoding RNAs (lncRNAs) can be widely involved in the regulation of many physiological processes, and have important roles in different stages of AS formation. LncRNAs can be secreted into the circulatory system through exosomes, microvesicles, and apoptotic bodies. Recently, increasing studies have been focused on the relationships between circulating lncRNAs and AS development. The lncRNAs in circulating blood are expected to be new non-invasive diagnostic markers for monitoring the progression of AS. We briefly reviewed the previously reported lncRNA transcripts which related to AS development and detectable in circulating blood, including ANRIL, SENCR, CoroMarker, LIPCAR, HIF1α-AS1, LncRNA H19, APPAT, KCNQ1OT1, LncPPARδ, LincRNA-p21, MALAT1, MIAT, and UCA1. Further researches and a definition of atherosclerosis-associated circulating lncRNA (ASCLncRNA) were also discussed.
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Affiliation(s)
- Shanshan Lu
- Department of Histology and Embryology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China
| | - Qin Liang
- Department of Histology and Embryology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China
| | - Yanqing Huang
- Department of Histology and Embryology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China
| | - Fanming Meng
- Department of Parasitology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China
| | - Junwen Liu
- Department of Histology and Embryology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China.,China-Africa Research Center of Infectious Diseases, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
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29
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Potalitsyn P, Selicharová I, Sršeň K, Radosavljević J, Marek A, Nováková K, Jiráček J, Žáková L. A radioligand binding assay for the insulin-like growth factor 2 receptor. PLoS One 2020; 15:e0238393. [PMID: 32877466 PMCID: PMC7467306 DOI: 10.1371/journal.pone.0238393] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/14/2020] [Indexed: 01/04/2023] Open
Abstract
Insulin-like growth factors 2 and 1 (IGF2 and IGF1) and insulin are closely related hormones that are responsible for the regulation of metabolic homeostasis, development and growth of the organism. Physiological functions of insulin and IGF1 are relatively well-studied, but information about the role of IGF2 in the body is still sparse. Recent discoveries called attention to emerging functions of IGF2 in the brain, where it could be involved in processes of learning and memory consolidation. It was also proposed that these functions could be mediated by the receptor for IGF2 (IGF2R). Nevertheless, little is known about the mechanism of signal transduction through this receptor. Here we produced His-tagged domain 11 (D11), an IGF2-binding element of IGF2R; we immobilized it on the solid support through a well-defined sandwich, consisting of neutravidin, biotin and synthetic anti-His-tag antibodies. Next, we prepared specifically radiolabeled [125I]-monoiodotyrosyl-Tyr2-IGF2 and optimized a sensitive and robust competitive radioligand binding assay for determination of the nanomolar binding affinities of hormones for D11 of IGF2. The assay will be helpful for the characterization of new IGF2 mutants to study the functions of IGF2R and the development of new compounds for the treatment of neurological disorders.
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Affiliation(s)
- Pavlo Potalitsyn
- Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic
- Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic
| | - Irena Selicharová
- Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic
| | - Kryštof Sršeň
- Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic
| | - Jelena Radosavljević
- Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic
| | - Aleš Marek
- Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic
| | - Kateřina Nováková
- Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic
| | - Jiří Jiráček
- Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic
| | - Lenka Žáková
- Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic
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30
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Muhammad T, Li M, Wang J, Huang T, Zhao S, Zhao H, Liu H, Chen ZJ. Roles of insulin-like growth factor II in regulating female reproductive physiology. SCIENCE CHINA-LIFE SCIENCES 2020; 63:849-865. [PMID: 32291558 DOI: 10.1007/s11427-019-1646-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 03/12/2020] [Indexed: 12/20/2022]
Abstract
The number of growth factors involved in female fertility has been extensively studied, but reluctance to add essential growth factors in culture media has limited progress in optimizing embryonic growth and implantation outcomes, a situation that has ultimately led to reduced pregnancy outcomes. Insulin-like growth factor II (IGF-II) is the most intricately regulated of all known reproduction-related growth factors characterized to date, and is perhaps the predominant growth factor in human ovarian follicles. This review aims to concisely summarize what is known about the role of IGF-II in follicular development, oocyte maturation, embryonic development, implantation success, placentation, fetal growth, and in reducing placental cell apoptosis, as well as present strategies that use growth factors in culture systems to improve the developmental potential of oocytes and embryos in different species. Synthesizing the present knowledge about the physiological roles of IGF-II in follicular development, oocyte maturation, and early embryonic development should, on the one hand, deepen our overall understanding of the potential beneficial effects of growth factors in female reproduction and on the other hand support development (optimization) of improved outcomes for assisted reproductive technologies.
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Affiliation(s)
- Tahir Muhammad
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, China.,Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, China.,Shandong Provincial Clinical Medicine Research Center for Reproductive Health, Shandong University, Jinan, 250012, China
| | - Mengjing Li
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, China.,Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, China.,Shandong Provincial Clinical Medicine Research Center for Reproductive Health, Shandong University, Jinan, 250012, China
| | - Jianfeng Wang
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, China.,Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, China.,Shandong Provincial Clinical Medicine Research Center for Reproductive Health, Shandong University, Jinan, 250012, China
| | - Tao Huang
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, China.,Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, China.,Shandong Provincial Clinical Medicine Research Center for Reproductive Health, Shandong University, Jinan, 250012, China
| | - Shigang Zhao
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, China.,Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, China.,Shandong Provincial Clinical Medicine Research Center for Reproductive Health, Shandong University, Jinan, 250012, China
| | - Han Zhao
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, China.,Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, China.,Shandong Provincial Clinical Medicine Research Center for Reproductive Health, Shandong University, Jinan, 250012, China
| | - Hongbin Liu
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China. .,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, China. .,Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, China. .,Shandong Provincial Clinical Medicine Research Center for Reproductive Health, Shandong University, Jinan, 250012, China.
| | - Zi-Jiang Chen
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China. .,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, 250012, China. .,Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, China. .,Shandong Provincial Clinical Medicine Research Center for Reproductive Health, Shandong University, Jinan, 250012, China. .,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, 200000, China. .,Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200000, China.
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Abrantes MA, Valencia AM, Bany-Mohammed F, Aranda JV, Beharry KD. Intergenerational Influence of Antenatal Betamethasone on Growth, Growth Factors, and Neurological Outcomes in Rats. Reprod Sci 2020; 27:418-431. [PMID: 32046399 DOI: 10.1007/s43032-019-00073-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 05/08/2019] [Indexed: 02/07/2023]
Abstract
Antenatal steroids suppress growth in the fetus and newborn. Although weight deficits are regained by weaning, studies show that intrauterine growth restriction with postnatal "catch-up" growth is a risk factor for hypertension, insulin resistance, and ischemic heart disease in adult life, with multigenerational consequences. We tested the hypothesis that fetal exposure to betamethasone suppresses fetal growth in the F1 pups and their untreated F2 offspring. Timed pregnant rats received a single two-dose course of intramuscular betamethasone (0.25 mg/kg/day) on days 17 and 18 of gestation. Matched controls received equivalent volumes sterile normal saline. The first-generation (F1) offspring were studied at term, P21, and P70, or mated at P60 to produce the following subgroups: (1) saline male/saline female (SM/SF), (2) betamethasone (B) male/BFemale (BM/BF), (3) BM/SF, and (4) SM/BF. The unexposed second-generation (F2) offspring were examined at birth and P70. Growth, neurological outcomes, and growth factors were determined. At birth, the F1 pups exposed to B were significantly growth suppressed compared with the controls, with correspondingly lower blood glucose, insulin, IGF-I, corticosterone, and leptin levels and delayed neurological outcomes. Catchup growth occurred at P21, surpassing that of the control group. By P70, growth was comparable, but glucose was higher, insulin was lower, and memory was retarded in the B group, and transmitted to the unexposed F2 offspring of B-exposed rats. Antenatal betamethasone has sustained metabolic and neurological effects that may impact the unexposed offspring. Whether these intergenerational effects reverse in future generations remain to be determined.
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Affiliation(s)
- Maria A Abrantes
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of California, Irvine Medical Center, Orange, CA, USA.,Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Long Beach Memorial Medical Center, Long Beach, CA, USA.,Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Kaiser Permanente, Irvine, CA, USA
| | - Arwin M Valencia
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of California, Irvine Medical Center, Orange, CA, USA.,Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Long Beach Memorial Medical Center, Long Beach, CA, USA.,Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Saddleback Memorial Medical Center, Laguna Hills, CA, USA
| | - Fayez Bany-Mohammed
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Long Beach Memorial Medical Center, Long Beach, CA, USA
| | - Jacob V Aranda
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA.,Department of Ophthalmology, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
| | - Kay D Beharry
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of California, Irvine Medical Center, Orange, CA, USA. .,Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Long Beach Memorial Medical Center, Long Beach, CA, USA. .,Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA. .,Department of Ophthalmology, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA. .,Departments of Pediatrics & Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA. .,Department of Pediatrics & Ophthalmology, Neonatal-Perinatal Medicine Clinical & Translational Research Labs, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Box 49, Brooklyn, NY, 11203, USA.
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32
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Pardo M, Cheng Y, Sitbon YH, Lowell JA, Grieco SF, Worthen RJ, Desse S, Barreda-Diaz A. Insulin growth factor 2 (IGF2) as an emergent target in psychiatric and neurological disorders. Review. Neurosci Res 2019; 149:1-13. [PMID: 30389571 DOI: 10.1016/j.neures.2018.10.012] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 10/05/2018] [Accepted: 10/29/2018] [Indexed: 12/23/2022]
Abstract
Insulin-like growth factor 2 (IGF2) is abundantly expressed in the central nervous system (CNS). Recent evidence highlights the role of IGF2 in the brain, sustained by data showing its alterations as a common feature across a variety of psychiatric and neurological disorders. Previous studies emphasize the potential role of IGF2 in psychiatric and neurological conditions as well as in memory impairments, targeting IGF2 as a pro-cognitive agent. New research on animal models supports that upcoming investigations should explore IGF2's strong promising role as a memory enhancer. The lack of effective treatments for cognitive disturbances as a result of psychiatric diseases lead to further explore IGF2 as a promising target for the development of new pharmacology for the treatment of memory dysfunctions. In this review, we aim at gathering all recent relevant studies and findings on the role of IGF2 in the development of psychiatric diseases that occur with cognitive problems.
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Affiliation(s)
- M Pardo
- University of Miami Miller School of Medicine, Department of Neurology, Miami, FL, USA.
| | - Y Cheng
- University of California Los Angeles, Neurology Department, Los Angeles, CA, USA.
| | - Y H Sitbon
- University of Miami Miller School of Medicine, Department of Molecular and Cellular Pharmacology, Miami, FL, USA.
| | - J A Lowell
- University of Miami, Department of Psychiatry & Behavioral Sciences, Miami, FL, USA.
| | - S F Grieco
- University of California, Department of Anatomy and Neurobiology, Irvine, CA, USA.
| | - R J Worthen
- University of Miami, Department of Psychiatry & Behavioral Sciences, Miami, FL, USA.
| | - S Desse
- University of Miami, Department of Psychiatry & Behavioral Sciences, Miami, FL, USA.
| | - A Barreda-Diaz
- University of Miami Miller School of Medicine, Department of Neurology, Miami, FL, USA.
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Borchiellini M, Ummarino S, Di Ruscio A. The Bright and Dark Side of DNA Methylation: A Matter of Balance. Cells 2019; 8:cells8101243. [PMID: 31614870 PMCID: PMC6830319 DOI: 10.3390/cells8101243] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/06/2019] [Accepted: 10/10/2019] [Indexed: 12/11/2022] Open
Abstract
DNA methylation controls several cellular processes, from early development to old age, including biological responses to endogenous or exogenous stimuli contributing to disease transition. As a result, minimal DNA methylation changes during developmental stages drive severe phenotypes, as observed in germ-line imprinting disorders, while genome-wide alterations occurring in somatic cells are linked to cancer onset and progression. By summarizing the molecular events governing DNA methylation, we focus on the methods that have facilitated mapping and understanding of this epigenetic mark in healthy conditions and diseases. Overall, we review the bright (health-related) and dark (disease-related) side of DNA methylation changes, outlining how bulk and single-cell genomic analyses are moving toward the identification of new molecular targets and driving the development of more specific and less toxic demethylating agents.
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Affiliation(s)
- Marta Borchiellini
- Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy.
- Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy.
| | - Simone Ummarino
- Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA 02115, USA.
| | - Annalisa Di Ruscio
- Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy.
- Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA 02115, USA.
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Genome imprinting in stem cells: A mini-review. Gene Expr Patterns 2019; 34:119063. [PMID: 31279979 DOI: 10.1016/j.gep.2019.119063] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 05/21/2019] [Accepted: 06/30/2019] [Indexed: 12/19/2022]
Abstract
Genomic imprinting is an epigenetic process result in silencing of one of the two alleles (maternal or paternal) based on the parent of origin. Dysregulation of imprinted genes results in detectable developmental and differential abnormalities. Epigenetics erasure is required for resetting the cell identity to a ground state during the production of induced pluripotent stem (iPS) cells from somatic cells. There are some contradictory reports regarding the status of the imprinting marks in the genome of iPS cells. Additionally, many studies highlighted the existence of subtle differences in the imprinting loci between different types of iPS cells and embryonic stem (ES) cells. These observations could ultimately undermine the use of patient-derived iPS cells for regenerative medicine.
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Baral K, Rotwein P. The insulin-like growth factor 2 gene in mammals: Organizational complexity within a conserved locus. PLoS One 2019; 14:e0219155. [PMID: 31251794 PMCID: PMC6599137 DOI: 10.1371/journal.pone.0219155] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 06/17/2019] [Indexed: 01/10/2023] Open
Abstract
The secreted protein, insulin-like growth factor 2 (IGF2), plays a central role in fetal and prenatal growth and development, and is regulated at the genetic level by parental imprinting, being expressed predominantly from the paternally derived chromosome in mice and humans. Here, IGF2/Igf2 and its locus has been examined in 19 mammals from 13 orders spanning ~166 million years of evolutionary development. By using human or mouse DNA segments as queries in genome analyses, and by assessing gene expression using RNA-sequencing libraries, more complexity was identified within IGF2/Igf2 than was annotated previously. Multiple potential 5’ non-coding exons were mapped in most mammals and are presumably linked to distinct IGF2/Igf2 promoters, as shown for several species by interrogating RNA-sequencing libraries. DNA similarity was highest in IGF2/Igf2 coding exons; yet, even though the mature IGF2 protein was conserved, versions of 67 or 70 residues are produced secondary to species-specific maintenance of alternative RNA splicing at a variable intron-exon junction. Adjacent H19 was more divergent than IGF2/Igf2, as expected in a gene for a noncoding RNA, and was identified in only 10/19 species. These results show that common features, including those defining IGF2/Igf2 coding and several non-coding exons, were likely present at the onset of the mammalian radiation, but that others, such as a putative imprinting control region 5’ to H19 and potential enhancer elements 3’ to H19, diversified with speciation. This study also demonstrates that careful analysis of genomic and gene expression repositories can provide new insights into gene structure and regulation.
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Affiliation(s)
- Kabita Baral
- Graduate School, College of Science, University of Texas at El Paso, El Paso, Texas
| | - Peter Rotwein
- Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech Health University Health Sciences Center, El Paso, Texas
- * E-mail:
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Hoch D, Gauster M, Hauguel-de Mouzon S, Desoye G. Diabesity-associated oxidative and inflammatory stress signalling in the early human placenta. Mol Aspects Med 2019; 66:21-30. [DOI: 10.1016/j.mam.2018.11.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 11/08/2018] [Accepted: 11/30/2018] [Indexed: 12/17/2022]
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Ziegler AN, Feng Q, Chidambaram S, Testai JM, Kumari E, Rothbard DE, Constancia M, Sandovici I, Cominski T, Pang K, Gao N, Wood TL, Levison SW. Insulin-like Growth Factor II: An Essential Adult Stem Cell Niche Constituent in Brain and Intestine. Stem Cell Reports 2019; 12:816-830. [PMID: 30905741 PMCID: PMC6450461 DOI: 10.1016/j.stemcr.2019.02.011] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 02/19/2019] [Accepted: 02/20/2019] [Indexed: 02/02/2023] Open
Abstract
Tissue-specific stem cells have unique properties and growth requirements, but a small set of juxtacrine and paracrine signals have been identified that are required across multiple niches. Whereas insulin-like growth factor II (IGF-II) is necessary for prenatal growth, its role in adult stem cell physiology is largely unknown. We show that loss of Igf2 in adult mice resulted in a ∼50% reduction in slowly dividing, label-retaining cells in the two regions of the brain that harbor neural stem cells. Concordantly, induced Igf2 deletion increased newly generated neurons in the olfactory bulb accompanied by hyposmia, and caused impairments in learning and memory and increased anxiety. Induced Igf2 deletion also resulted in rapid loss of stem and progenitor cells in the crypts of Lieberkühn, leading to body-weight loss and lethality and the inability to produce organoids in vitro. These data demonstrate that IGF-II is critical for multiple adult stem cell niches.
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Affiliation(s)
- Amber N. Ziegler
- Department Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Qiang Feng
- Department of Biological Sciences, Rutgers University-Newark, Newark, NJ 07102, USA
| | - Shravanthi Chidambaram
- Department Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Jaimie M. Testai
- Department Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Ekta Kumari
- Department Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Deborah E. Rothbard
- Department Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Miguel Constancia
- University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Department of Obstetrics and Gynaecology, Cambridge CB2 0SW, UK,National Institute for Health Research Cambridge Biomedical Research Centre, The University of Cambridge, Cambridge CB2 0SW, UK,Centre for Trophoblast Research, The University of Cambridge, Cambridge CB2 0SW, UK
| | - Ionel Sandovici
- University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Department of Obstetrics and Gynaecology, Cambridge CB2 0SW, UK,Centre for Trophoblast Research, The University of Cambridge, Cambridge CB2 0SW, UK
| | - Tara Cominski
- Department Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Kevin Pang
- Department Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Nan Gao
- Department of Biological Sciences, Rutgers University-Newark, Newark, NJ 07102, USA
| | - Teresa L. Wood
- Department Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Steven W. Levison
- Department Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA,Corresponding author
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Grosse G, Hilger A, Ludwig M, Reutter H, Lorenzen F, Even G, Holterhus PM, Woelfle J. Targeted Resequencing of Putative Growth-Related Genes Using Whole Exome Sequencing in Patients with Severe Primary IGF-I Deficiency. Horm Res Paediatr 2018; 88:408-417. [PMID: 29073591 DOI: 10.1159/000480505] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 08/21/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND/AIMS To elucidate the genetic causes of severe primary insulin-like growth factor-I deficiency (SPIGFD) by systematic, targeted, next-generation sequencing (NGS)-based resequencing of growth-related genes. METHODS Clinical phenotyping followed by NGS in 17 families including 6 affected sib pairs. RESULTS We identified disease-causing, heterozygous, de novo variants in HRAS (p.Gly13Cys) and FAM111A (p.Arg569His) in 2 male patients with syndromic SPIGFD. A previously described homozygous GHR nonsense variant was detected in 2 siblings of a consanguineous family (p.Glu198*). Furthermore, we identified an inherited novel variant in the IGF2 gene (p.Arg156Cys) of a maternally imprinted gene in a less severely affected father and his affected daughter. We detected 2 other novel missense variants in SH2B1 and SOCS2, both were inherited from an unaffected parent. CONCLUSIONS Screening of growth-related genes using NGS-based, large-scale, targeted resequencing identified disease-causing variants in HRAS, FAM111A, and GHR. Considering the increased risk of subjects with HRAS mutations for neoplasms, close clinical monitoring and a thorough discussion of the risk/benefit ratio of the treatment with recombinant IGF-I is mandatory. Segregation analysis proved to be critical in the interpretation of potential SPIGFD-associated gene variations.
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Affiliation(s)
- Greta Grosse
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Alina Hilger
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Michael Ludwig
- Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
| | - Heiko Reutter
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Children's Hospital, Department of Pediatrics, University of Bonn, Bonn, Germany
| | | | - Gertrud Even
- Children's Hospital, Pediatric Endocrinology Division, University of Cologne, Cologne, Germany
| | - Paul-Martin Holterhus
- Children's Hospital, Pediatric Endocrinology Division, University of Kiel, Kiel, Germany
| | - Joachim Woelfle
- Children's Hospital, Department of Pediatrics, University of Bonn, Bonn, Germany,
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Goodman SJ, Roubinov DS, Bush NR, Park M, Farré P, Emberly E, Hertzman C, Essex MJ, Kobor MS, Boyce WT. Children's biobehavioral reactivity to challenge predicts DNA methylation in adolescence and emerging adulthood. Dev Sci 2018; 22:e12739. [PMID: 30176105 PMCID: PMC6433477 DOI: 10.1111/desc.12739] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 08/08/2018] [Indexed: 12/21/2022]
Abstract
A growing body of research has documented associations between adverse childhood environments and DNA methylation, highlighting epigenetic processes as potential mechanisms through which early external contexts influence health across the life course. The present study tested a complementary hypothesis: indicators of children's early internal, biological, and behavioral responses to stressful challenges may also be linked to stable patterns of DNA methylation later in life. Children's autonomic nervous system reactivity, temperament, and mental health symptoms were prospectively assessed from infancy through early childhood, and principal components analysis (PCA) was applied to derive composites of biological and behavioral reactivity. Buccal epithelial cells were collected from participants at 15 and 18 years of age. Findings revealed an association between early life biobehavioral inhibition/disinhibition and DNA methylation across many genes. Notably, reactive, inhibited children were found to have decreased DNA methylation of the DLX5 and IGF2 genes at both time points, as compared to non‐reactive, disinhibited children. Results of the present study are provisional but suggest that the gene's profile of DNA methylation may constitute a biomarker of normative or potentially pathological differences in reactivity. Overall, findings provide a foundation for future research to explore relations among epigenetic processes and differences in both individual‐level biobehavioral risk and qualities of the early, external childhood environment.
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Affiliation(s)
- Sarah J Goodman
- Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research, Vancouver, BC, Canada.,Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | | | - Nicole R Bush
- Psychiatry, University of California, San Francisco, California.,Pediatrics, University of California, San Francisco, California
| | - Mina Park
- Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research, Vancouver, BC, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
| | - Pau Farré
- Physics, Simon Fraser University, Burnaby, BC, Canada
| | - Eldon Emberly
- Physics, Simon Fraser University, Burnaby, BC, Canada
| | - Clyde Hertzman
- School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.,Human Early Learning Partnership, University of British Columbia, Vancouver, BC, Canada
| | - Marilyn J Essex
- Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Michael S Kobor
- Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research, Vancouver, BC, Canada.,Medical Genetics, University of British Columbia, Vancouver, BC, Canada.,Human Early Learning Partnership, University of British Columbia, Vancouver, BC, Canada.,Child and Brain Development Program, Canadian Institute for Advanced Research, Toronto, ON, Canada
| | - W Thomas Boyce
- Psychiatry, University of California, San Francisco, California.,Pediatrics, University of California, San Francisco, California.,Child and Brain Development Program, Canadian Institute for Advanced Research, Toronto, ON, Canada
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Rotwein P. The insulin-like growth factor 2 gene and locus in nonmammalian vertebrates: Organizational simplicity with duplication but limited divergence in fish. J Biol Chem 2018; 293:15912-15932. [PMID: 30154247 DOI: 10.1074/jbc.ra118.004861] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 08/16/2018] [Indexed: 01/28/2023] Open
Abstract
The small, secreted peptide, insulin-like growth factor 2 (IGF2), is essential for fetal and prenatal growth in humans and other mammals. Human IGF2 and mouse Igf2 genes are located within a conserved linkage group and are regulated by parental imprinting, with IGF2/Igf2 being expressed from the paternally derived chromosome, and H19 from the maternal chromosome. Here, data retrieved from genomic and gene expression repositories were used to examine the Igf2 gene and locus in 8 terrestrial vertebrates, 11 ray-finned fish, and 1 lobe-finned fish representing >500 million years of evolutionary diversification. The analysis revealed that vertebrate Igf2 genes are simpler than their mammalian counterparts, having fewer exons and lacking multiple gene promoters. Igf2 genes are conserved among these species, especially in protein-coding regions, and IGF2 proteins also are conserved, although less so in fish than in terrestrial vertebrates. The Igf2 locus in terrestrial vertebrates shares additional genes with its mammalian counterparts, including tyrosine hydroxylase (Th), insulin (Ins), mitochondrial ribosomal protein L23 (Mrpl23), and troponin T3, fast skeletal type (Tnnt3), and both Th and Mrpl23 are present in the Igf2 locus in fish. Taken together, these observations support the idea that a recognizable Igf2 was present in the earliest vertebrate ancestors, but that other features developed and diversified in the gene and locus with speciation, especially in mammals. This study also highlights the need for correcting inaccuracies in genome databases to maximize our ability to accurately assess contributions of individual genes and multigene families toward evolution, physiology, and disease.
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Affiliation(s)
- Peter Rotwein
- From the Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech Health University Health Sciences Center, El Paso, Texas 79905
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Ghanipoor-Samami M, Javadmanesh A, Burns BM, Thomsen DA, Nattrass GS, Estrella CAS, Kind KL, Hiendleder S. Atlas of tissue- and developmental stage specific gene expression for the bovine insulin-like growth factor (IGF) system. PLoS One 2018; 13:e0200466. [PMID: 30001361 PMCID: PMC6042742 DOI: 10.1371/journal.pone.0200466] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 06/27/2018] [Indexed: 01/04/2023] Open
Abstract
The insulin-like growth factor (IGF) axis is fundamental for mammalian growth and development. However, no comprehensive reference data on gene expression across tissues and pre- and postnatal developmental stages are available for any given species. Here we provide systematic promoter- and splice variant specific information on expression of IGF system components in embryonic (Day 48), fetal (Day 153), term (Day 277, placenta) and juvenile (Day 365–396) tissues of domestic cow, a major agricultural species and biomedical model. Analysis of spatiotemporal changes in expression of IGF1, IGF2, IGF1R, IGF2R, IGFBP1-8 and IR genes, as well as lncRNAs H19 and AIRN, by qPCR, indicated an overall increase in expression from embryo to fetal stage, and decrease in expression from fetal to juvenile stage. The stronger decrease in expression of lncRNAs (average ―16-fold) and ligands (average ―12.1-fold) compared to receptors (average ―5.7-fold) and binding proteins (average ―4.3-fold) is consistent with known functions of IGF peptides and supports important roles of lncRNAs in prenatal development. Pronounced overall reduction in postnatal expression of IGF system components in lung (―12.9-fold) and kidney (―13.2-fold) are signatures of major changes in organ function while more similar hepatic expression levels (―2.2-fold) are evidence of the endocrine rather than autocrine/paracrine role of IGFs in postnatal growth regulation. Despite its rapid growth, placenta displayed a more stable expression pattern than other organs during prenatal development. Quantitative analyses of contributions of promoters P0-P4 to global IGF2 transcript in fetal tissues revealed that P4 accounted for the bulk of transcript in all tissues but skeletal muscle. Demonstration of IGF2 expression in fetal muscle and postnatal liver from a promoter orthologous to mouse and human promoter P0 provides further evidence for an evolutionary and developmental shift from placenta-specific P0-expression in rodents and suggests that some aspects of bovine IGF expression may be closer to human than mouse.
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Affiliation(s)
- Mani Ghanipoor-Samami
- Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- JS Davies Epigenetics and Genetics Group, Davies Research Centre, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, South Australia, Australia
| | - Ali Javadmanesh
- Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- JS Davies Epigenetics and Genetics Group, Davies Research Centre, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, South Australia, Australia
| | - Brian M. Burns
- Centre for Animal Science, Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, Rockhampton, Queensland, Australia
| | - Dana A. Thomsen
- Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- JS Davies Epigenetics and Genetics Group, Davies Research Centre, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, South Australia, Australia
| | - Greg S. Nattrass
- Livestock Systems, South Australian Research and Development Institute (SARDI), Roseworthy, South Australia, Australia
| | - Consuelo Amor S. Estrella
- Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- JS Davies Epigenetics and Genetics Group, Davies Research Centre, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, South Australia, Australia
| | - Karen L. Kind
- JS Davies Epigenetics and Genetics Group, Davies Research Centre, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, South Australia, Australia
| | - Stefan Hiendleder
- Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- JS Davies Epigenetics and Genetics Group, Davies Research Centre, School of Animal and Veterinary Sciences, Roseworthy Campus, The University of Adelaide, Roseworthy, South Australia, Australia
- * E-mail:
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Binder G, Eggermann T, Weber K, Ferrand N, Schweizer R. The Diagnostic Value of IGF-2 and the IGF/IGFBP-3 System in Silver-Russell Syndrome. Horm Res Paediatr 2018; 88:201-207. [PMID: 28675902 DOI: 10.1159/000477666] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 05/19/2017] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Recently, we have described a family of 4 members presenting with intrauterine and postnatal growth failure, low IGF-2 levels, and signs of Silver-Russell syndrome (SRS) who carried a genomic IGF2 mutation. Here, we assess the value of IGF-2 in relation to SRS. METHODS We collected data from 48 SRS children and 48 short children born small for gestational age (SGA) seen at our center. The SRS children were 4.6 ± 2.0 years of age, and the SGA children were 4.8 ± 1.8 years of age. All patients were prepubertal and growth hormone naive. An 11p15 ICR1 loss of methylation (11p15LOM) was present in 22, maternal uniparental disomy of chromosome 7 (upd(7)mat) in 7, and IGF2 genomic mutation (IGF2mut) in 3 patients. Growth factors were measured by in-house radioimmunoassays. RESULTS The median IGF-2 standard deviation scores (SDSs) were: IGF2mut -1.75, upd(7)mat -1.69, nonsyndromic SGA -1.52, 11p15LOM -0.61, and clinical (tested negative) -0.55. The median IGF-2:IGF-1 concentration ratio was 2.57 in IGF2mut compared to 5.44 in 11p15LOM (p = 0.036), 7.84 in clinical, and 7.98 in upd(7)mat. Upd(7)mat patients had significantly lower IGF-1 and IGFBP-3 SDSs than patients with 11p15LOM (p ≤ 0.002). CONCLUSION Serum IGF-2 in combination with IGF-1 and IGFBP-3 can add to the clinical signs of SRS patients and help to perform targeted genetic testing. Further studies are needed.
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Affiliation(s)
- Gerhard Binder
- Pediatric Endocrinology, University Children's Hospital, Tübingen, Germany
| | | | - Karin Weber
- Pediatric Endocrinology, University Children's Hospital, Tübingen, Germany
| | - Nawfel Ferrand
- Pediatric Endocrinology, University Children's Hospital, Tübingen, Germany
| | - Roland Schweizer
- Pediatric Endocrinology, University Children's Hospital, Tübingen, Germany
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Rotwein P. Similarity and variation in the insulin-like growth factor 2 - H19 locus in primates. Physiol Genomics 2018; 50:425-439. [PMID: 29602297 PMCID: PMC6032289 DOI: 10.1152/physiolgenomics.00030.2018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 03/22/2018] [Accepted: 03/23/2018] [Indexed: 02/07/2023] Open
Abstract
Insulin-like growth factor 2 (IGF2), a small, secreted protein, is critical for fetal and prenatal growth in humans and other mammals. The IGF2 gene and its mouse homolog comprise part of a conserved linkage group that is regulated by parental imprinting, with IGF2/ Igf2 being expressed from the paternal chromosome, and the adjacent H19 gene from the maternal chromosome. By using information extracted from public genomic and gene expression databases, I have now analyzed this locus in nine nonhuman primate species representing over 60 million years of evolutionary divergence from a common progenitor. Both IGF2 and H19 genes and the entire locus have been conserved among these primates. Each primate IGF2 gene except for gibbon and marmoset is composed of 10 exons and contains five potential promoters, each with distinctive 5'-untranslated exons. Similarly, except for marmoset and mouse lemur, H19 consists of six exons and has two promoters. DNA sequence conservation is high, not only in orthologous exons and promoters, but also in a putative imprinting control region located 5' to H19 and in multiple potential distal enhancer elements found 3' to H19. Collectively, these results support the hypothesis that common regulatory processes shaped the IGF2 - H19 locus before the onset of primate speciation more than 85 million years ago. This study also leads to the conclusion that inaccuracies in data presentation in genetic repositories could limit our ability to develop novel insights about roles of individual genes and multigene loci in mammalian physiology and disease.
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Affiliation(s)
- Peter Rotwein
- Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech Health University Health Sciences Center , El Paso, Texas
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Lnc RNA H19 is associated with poor prognosis in breast cancer patients and promotes cancer stemness. Breast Cancer Res Treat 2018; 170:507-516. [DOI: 10.1007/s10549-018-4793-z] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 04/13/2018] [Indexed: 12/13/2022]
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Cowley M, Skaar DA, Jima DD, Maguire RL, Hudson KM, Park SS, Sorrow P, Hoyo C. Effects of Cadmium Exposure on DNA Methylation at Imprinting Control Regions and Genome-Wide in Mothers and Newborn Children. ENVIRONMENTAL HEALTH PERSPECTIVES 2018; 126:037003. [PMID: 29529597 PMCID: PMC6071808 DOI: 10.1289/ehp2085] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 01/30/2018] [Accepted: 01/30/2018] [Indexed: 05/21/2023]
Abstract
BACKGROUND Imprinted genes are defined by their preferential expression from one of the two parental alleles. This unique mode of gene expression is dependent on allele-specific DNA methylation profiles established at regulatory sequences called imprinting control regions (ICRs). These loci have been used as biosensors to study how environmental exposures affect methylation and transcription. However, a critical unanswered question is whether they are more, less, or equally sensitive to environmental stressors as the rest of the genome. OBJECTIVES Using cadmium exposure in humans as a model, we aimed to determine the relative sensitivity of ICRs to perturbation of methylation compared to similar, nonimprinted loci in the genome. METHODS We assayed DNA methylation genome-wide using bisulfite sequencing of 19 newborn cord blood and 20 maternal blood samples selected on the basis of maternal blood cadmium levels. Differentially methylated regions (DMRs) associated with cadmium exposure were identified. RESULTS In newborn cord blood and maternal blood, 641 and 1,945 cadmium-associated DMRs were identified, respectively. DMRs were more common at the 15 maternally methylated ICRs than at similar nonimprinted loci in newborn cord blood (p=5.64×10-8) and maternal blood (p=6.22×10-14), suggesting a higher sensitivity for ICRs to cadmium. Genome-wide, Enrichr analysis indicated that the top three functional categories for genes that overlapped DMRs in maternal blood were body mass index (BMI) (p=2.0×10-5), blood pressure (p=3.8×10-5), and body weight (p=0.0014). In newborn cord blood, the top three functional categories were BMI, atrial fibrillation, and hypertension, although associations were not significant after correction for multiple testing (p=0.098). These findings suggest that epigenetic changes may contribute to the etiology of cadmium-associated diseases. CONCLUSIONS We analyzed cord blood and maternal blood DNA methylation profiles genome-wide at nucleotide resolution in individuals selected for high and low blood cadmium levels in the first trimester. Our findings suggest that ICRs may be hot spots for perturbation by cadmium, motivating further study of these loci to investigate potential mechanisms of cadmium action. https://doi.org/10.1289/EHP2085.
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Affiliation(s)
- Michael Cowley
- Center for Human Health and the Environment and Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina, USA
- W.M. Keck Center for Behavioral Biology , North Carolina State University , Raleigh, North Carolina, USA
| | - David A Skaar
- Center for Human Health and the Environment and Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina, USA
| | - Dereje D Jima
- Center for Human Health and the Environment and Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina, USA
- Bioinformatics Research Center, North Carolina State University , Raleigh, North Carolina, USA
| | - Rachel L Maguire
- Center for Human Health and the Environment and Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina, USA
| | - Kathleen M Hudson
- Center for Human Health and the Environment and Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina, USA
| | - Sarah S Park
- Center for Human Health and the Environment and Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina, USA
| | - Patricia Sorrow
- Center for Human Health and the Environment and Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina, USA
| | - Cathrine Hoyo
- Center for Human Health and the Environment and Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina, USA
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Kikuchi K, Sasaki K, Akizawa H, Tsukahara H, Bai H, Takahashi M, Nambo Y, Hata H, Kawahara M. Identification and expression analysis of cDNA encoding insulin-like growth factor 2 in horses. J Reprod Dev 2018; 64:57-64. [PMID: 29151450 PMCID: PMC5830359 DOI: 10.1262/jrd.2017-124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Insulin-like growth factor 2 (IGF2) is responsible for a broad range of physiological processes during fetal development and adulthood, but genomic analyses of IGF2 containing the 5ʹ- and
3ʹ-untranslated regions (UTRs) in equines have been limited. In this study, we characterized the IGF2 mRNA containing the UTRs, and determined its expression pattern in the fetal tissues of horses. The
complete equine IGF2 mRNA sequence harboring another exon approximately 2.8 kb upstream from the canonical transcription start site was identified as a new transcript variant. As this upstream exon did
not contain the start codon, the amino acid sequence was identical to the canonical variant. Analysis of the deduced amino acid sequence revealed that the protein possessed two major domains, IlGF and IGF2_C, and
analysis of IGF2 sequence polymorphism in fetal tissues of Hokkaido native horse and Thoroughbreds revealed a single nucleotide polymorphism (T to C transition) at position 398 in Thoroughbreds, which
caused an amino acid substitution at position 133 in the IGF2 sequence. Furthermore, the expression pattern of the IGF2 mRNA in the fetal tissues of horses was determined for the first time, and was
found to be consistent with those of other species. Taken together, these results suggested that the transcriptional and translational products of the IGF2 gene have conserved functions in the fetal
development of mammals, including horses.
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Affiliation(s)
- Kohta Kikuchi
- Laboratory of Animal Genetics and Reproduction, Research Faculty of Agriculture, Hokkaido University, Hokkaido 060-8589, Japan
| | - Keisuke Sasaki
- Laboratory of Animal Genetics and Reproduction, Research Faculty of Agriculture, Hokkaido University, Hokkaido 060-8589, Japan.,Present: Department of Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan
| | - Hiroki Akizawa
- Laboratory of Animal Genetics and Reproduction, Research Faculty of Agriculture, Hokkaido University, Hokkaido 060-8589, Japan
| | - Hayato Tsukahara
- Laboratory of Animal Genetics and Reproduction, Research Faculty of Agriculture, Hokkaido University, Hokkaido 060-8589, Japan
| | - Hanako Bai
- Laboratory of Animal Genetics and Reproduction, Research Faculty of Agriculture, Hokkaido University, Hokkaido 060-8589, Japan
| | - Masashi Takahashi
- Laboratory of Animal Genetics and Reproduction, Research Faculty of Agriculture, Hokkaido University, Hokkaido 060-8589, Japan
| | - Yasuo Nambo
- Equine Science Division, Hidaka Training and Research Center, Japan Racing Association, Hokkaido 057-0171, Japan.,Present: Department of Clinical Veterinary Sciences, Obihiro University of Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan
| | - Hiroshi Hata
- Field Science Center for Northern Biosphere, Hokkaido University, Hokkaido 060-0811, Japan
| | - Manabu Kawahara
- Laboratory of Animal Genetics and Reproduction, Research Faculty of Agriculture, Hokkaido University, Hokkaido 060-8589, Japan
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Correlation of long non-coding RNA H19 expression with cisplatin-resistance and clinical outcome in lung adenocarcinoma. Oncotarget 2018; 8:2558-2567. [PMID: 27911863 PMCID: PMC5356823 DOI: 10.18632/oncotarget.13708] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 11/21/2016] [Indexed: 01/05/2023] Open
Abstract
The acquired drug resistance would influence the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer. The present study aimed to investigate the correlation of long non-coding RNA (lncRNA) H19 with cisplatin-resistance and clinical outcome in lung adenocarcinoma. In our study, the expression of H19 in cisplatin-resistant A549/DDP cells was unregulated. Knockdown of H19 restored the response of A549/DDP cells to cisplatin. H19-mediated chemosensitivity enhancement was associated with metastasis, induction of G0/G1 cell-cycle arrest, cell proliferation, and increased apoptosis. Furthermore, lncRNA H19 expression was significantly related to TNM stage and metastasis (P = 0.012). Overexpression of H19 was negatively correlated with cisplatin-based chemotherapy response in patients. Patients with high H19 expression exhibited a significantly shorter median progression-free survival (PFS) [4.7 months] than the low-expression patients (6.3months) [P = 0.002]. In summary, H19-mediated regulation of cisplatin resistance in human lung adenocarcinoma cells is demonstrated for the first time. H19 could potentially serve as a molecular marker to predict the clinical outcomes of lung adenocarcinoma patients.
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Brütting C, Narasimhan H, Hoffmann F, Kornhuber ME, Staege MS, Emmer A. Investigation of Endogenous Retrovirus Sequences in the Neighborhood of Genes Up-regulated in a Neuroblastoma Model after Treatment with Hypoxia-Mimetic Cobalt Chloride. Front Microbiol 2018. [PMID: 29515560 PMCID: PMC5826361 DOI: 10.3389/fmicb.2018.00287] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Human endogenous retroviruses (ERVs) have been found to be associated with different diseases, e.g., multiple sclerosis (MS). Most human ERVs integrated in our genome are not competent to replicate and these sequences are presumably silent. However, transcription of human ERVs can be reactivated, e.g., by hypoxia. Interestingly, MS has been linked to hypoxia since decades. As some patterns of demyelination are similar to white matter ischemia, hypoxic damage is discussed. Therefore, we are interested in the association between hypoxia and ERVs. As a model, we used human SH-SY5Y neuroblastoma cells after treatment with the hypoxia-mimetic cobalt chloride and analyzed differences in the gene expression profiles in comparison to untreated cells. The vicinity of up-regulated genes was scanned for endogenous retrovirus-derived sequences. Five genes were found to be strongly up-regulated in SH-SY5Y cells after treatment with cobalt chloride: clusterin, glutathione peroxidase 3, insulin-like growth factor 2, solute carrier family 7 member 11, and neural precursor cell expressed developmentally down-regulated protein 9. In the vicinity of these genes we identified large (>1,000 bp) open reading frames (ORFs). Most of these ORFs showed only low similarities to proteins from retro-transcribing viruses. However, we found very high similarity between retrovirus envelope sequences and a sequence in the vicinity of neural precursor cell expressed developmentally down-regulated protein 9. This sequence encodes the human endogenous retrovirus group FRD member 1, the encoded protein product is called syncytin 2. Transfection of syncytin 2 into the well-characterized Ewing sarcoma cell line A673 was not able to modulate the low immunostimulatory activity of this cell line. Future research is needed to determine whether the identified genes and the human endogenous retrovirus group FRD member 1 might play a role in the etiology of MS.
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Affiliation(s)
- Christine Brütting
- Department of Surgical and Conservative Paediatrics and Adolescent Medicine, Martin Luther University of Halle-Wittenberg, Halle, Germany.,Department of Neurology, Martin Luther University of Halle-Wittenberg, Halle, Germany
| | - Harini Narasimhan
- Department of Surgical and Conservative Paediatrics and Adolescent Medicine, Martin Luther University of Halle-Wittenberg, Halle, Germany
| | - Frank Hoffmann
- Department of Neurology, Hospital "Martha-Maria" Halle-Dölau, Halle, Germany
| | - Malte E Kornhuber
- Department of Neurology, Martin Luther University of Halle-Wittenberg, Halle, Germany
| | - Martin S Staege
- Department of Surgical and Conservative Paediatrics and Adolescent Medicine, Martin Luther University of Halle-Wittenberg, Halle, Germany
| | - Alexander Emmer
- Department of Neurology, Martin Luther University of Halle-Wittenberg, Halle, Germany
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50
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Rotwein P. The complex genetics of human insulin-like growth factor 2 are not reflected in public databases. J Biol Chem 2018; 293:4324-4333. [PMID: 29414792 DOI: 10.1074/jbc.ra117.001573] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 01/15/2018] [Indexed: 01/02/2023] Open
Abstract
Recent advances in genetics present unique opportunities for enhancing knowledge about human physiology and disease susceptibility. Understanding this information at the individual gene level is challenging and requires extracting, collating, and interpreting data from a variety of public gene repositories. Here, I illustrate this challenge by analyzing the gene for human insulin-like growth factor 2 (IGF2) through the lens of several databases. IGF2, a 67-amino acid secreted peptide, is essential for normal prenatal growth and is involved in other physiological and pathophysiological processes in humans. Surprisingly, none of the genetic databases accurately described or completely delineated human IGF2 gene structure or transcript expression, even though all relevant information could be found in the published literature. Although IGF2 shares multiple features with the mouse Igf2 gene, it has several unique properties, including transcription from five promoters. Both genes undergo parental imprinting, with IGF2/Igf2 being expressed primarily from the paternal chromosome and the adjacent H19 gene from the maternal chromosome. Unlike mouse Igf2, whose expression declines after birth, human IGF2 remains active throughout life. This characteristic has been attributed to a unique human gene promoter that escapes imprinting, but as shown here, it involves several different promoters with distinct tissue-specific expression patterns. Because new testable hypotheses could lead to critical insights into IGF2 actions in human physiology and disease, it is incumbent that our fundamental understanding is accurate. Similar challenges affecting knowledge of other human genes should promote attempts to critically evaluate, interpret, and correct human genetic data in publicly available databases.
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Affiliation(s)
- Peter Rotwein
- From the Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech Health University Health Sciences Center, El Paso, Texas 79905
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