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Hannon Bozorgmehr J. The De Novo Emergence of Two Brain Genes in the Human Lineage Appears to be Unsupported. J Mol Evol 2025; 93:3-10. [PMID: 39725692 DOI: 10.1007/s00239-024-10227-3] [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: 10/04/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024]
Abstract
Recently, certain studies have claimed that cognitive features and pathologies unique to humans can be traced to certain changes in the nervous system. These are caused by genes that have likely evolved "from scratch," not having any coding precursors. The translated proteins would not appear outside of the human lineage and any orthologs in other species should be non-coding. This contrasts with research that has identified a decisive role for duplication, and modifications to regulatory sequences, for such phenotypic traits. Closer examination, however, reveals that the inferred lineage-specific emergence of at least two of these genes is likely a misinterpretation owing to a lack of peptide verification, experimental oversights, and insufficient species comparisons. A possible pseudogenic origin is proposed for one of them. The implications of these claims for the study of molecular evolution are discussed.
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2
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Skinner CM, Conboy MJ, Conboy IM. DNA methylation clocks struggle to distinguish inflammaging from healthy aging, but feature rectification improves coherence and enhances detection of inflammaging. GeroScience 2025:10.1007/s11357-024-01460-1. [PMID: 39825170 DOI: 10.1007/s11357-024-01460-1] [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: 10/10/2024] [Accepted: 11/26/2024] [Indexed: 01/20/2025] Open
Abstract
Biological age estimation from DNA methylation and determination of relevant biomarkers is an active research problem which has predominantly been tackled with black-box penalized regression. Machine learning is used to select a small subset of features from hundreds of thousands of CpG probes and to increase generalizability typically lacking with ordinary least-squares regression. Here, we show that such feature selection lacks biological interpretability and relevance in the clocks of the first and next generations and clarify the logic by which these clocks systematically exclude biomarkers of aging and age-related disease. Moreover, in contrast to the assumption that regularized linear regression is needed to prevent overfitting, we demonstrate that hypothesis-driven selection of biologically relevant features in conjunction with ordinary least squares regression yields accurate, well-calibrated, generalizable clocks with high interpretability. We further demonstrate that the interplay of inflammaging-related shifts of predictor values and their corresponding weights, which we term feature shifts, contributes to the lack of resolution between health and inflammaging in conventional linear models. Lastly, we introduce a method of feature rectification, which aligns these shifts to improve the distinction of age predictions for healthy people vs. patients with various chronic inflammation diseases.
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Affiliation(s)
- Colin M Skinner
- Department of Bioengineering and QB3, University of California, Berkeley, Berkeley, CA, 94720, USA
| | - Michael J Conboy
- Department of Bioengineering and QB3, University of California, Berkeley, Berkeley, CA, 94720, USA
| | - Irina M Conboy
- Department of Bioengineering and QB3, University of California, Berkeley, Berkeley, CA, 94720, USA.
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3
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Wu J, Zhang C, Li H, Zhang S, Chen J, Qin L. Competing endogenous RNAs network dysregulation in oral cancer: a multifaceted perspective on crosstalk and competition. Cancer Cell Int 2024; 24:431. [PMID: 39725978 DOI: 10.1186/s12935-024-03580-2] [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: 04/26/2024] [Accepted: 11/19/2024] [Indexed: 12/28/2024] Open
Abstract
Oral cancer progresses from asymptomatic to advanced stages, often involving cervical lymph node metastasis, resistance to chemotherapy, and an unfavorable prognosis. Clarifying its potential mechanisms is vital for developing effective theraputic strategies. Recent research suggests a substantial involvement of non-coding RNA (ncRNA) in the initiation and advancement of oral cancer. However, the underlying roles and functions of various ncRNA types in the growth of this malignant tumor remain unclear. Competing endogenous RNAs (ceRNAs) refer to transcripts that can mutually regulate each other at the post-transcriptional level by vying for shared miRNAs. Networks of ceRNAs establish connections between the functions of protein-coding mRNAs and non-coding RNAs, including microRNA, long non-coding RNA, pseudogenic RNA, and circular RNA, piwi-RNA, snoRNA. A growing body of research has indicated that imbalances in ceRNAs networks play a crucial role in various facets of oral cancer, including development, metastasis, migration, invasion, and inflammatory responses. Hence, delving into the regulatory pathways of ceRNAs in oral cancer holds the potential to advance our understanding of the pathological mechanisms, facilitate early diagnosis, and foster targeted drug development for this malignancy. The present review summarized the fundamental role of ceRNA network, discussed the limitations of current ceRNA applications, which have been improved through chemical modification and carrier delivery as new biomarkers for diagnosis and prognosis is expected to offer a groundbreaking therapeutic approach for individuals with oral cancer.
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Affiliation(s)
- Jiajun Wu
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Chanjuan Zhang
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Hongfang Li
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Shuo Zhang
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Jingxin Chen
- Department of Oral and Maxillofacial Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, 570311, China.
- School of Pharmacy, Hunan University of Chinese Medicine, 300 Xueshi Road, Hanpu Science and Education District, Changsha, Hunan, 410208, China.
| | - Li Qin
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
- Hunan Provincial Key Laboratory of Vascular Biology and Translational Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
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4
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Zhang F, Wan W, Li Y, Wang B, Shao Y, Di X, Zhang H, Cai W, Wei Y, Ma X. Construction of a Full-Length transcriptome resource for the African sharptooth catfish (Clarias gariepinus), a prototypical air-breathing Fish, based on isoform sequencing (Iso-Seq). Gene 2024; 930:148802. [PMID: 39094712 DOI: 10.1016/j.gene.2024.148802] [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: 05/02/2024] [Revised: 07/12/2024] [Accepted: 07/25/2024] [Indexed: 08/04/2024]
Abstract
The African sharptooth catfish (Clarias gariepinus) assumes significance in aquaculture, given its role as a farmed freshwater species with modified gill structures functioning as an air-breathing organ (ABO). To provide a scientific basis for further elucidating the air-breathing formation mechanism and deeply utilizing the genetic resources of Clarias gariepinus, we utilized the PacBio sequencing platform to acquire a comprehensive full-length transcriptome from five juvenile developmental stages and various adult tissues, including the ABO, gills, liver, skin, and muscle. We generated 25,766,688 high-quality reads, with an average length of 2,006 bp and an N50 of 2,241 bp. Following rigorous quality control, 34,890 (97.7 %) of the high-quality isoforms were mapped to the reference genome for gene and transcript annotation, yielding 387 novel isoforms and 14,614 new isoforms. Additionally, we identified 28,582 open reading frames, 48 SNPs, 5,464 variable splices, and 6,141 variable polyadenylation sites, along with 475 long non-coding RNAs. Many DEGs were involved with low oxygen GO terms and KEGG pathways, such as response to stimulus, biological regulation and catalytic activities. Furthermore, it was found that transcription factors such as zf-C2H2, Homeobox, bHLH, and MYB could underpin the African sharptooth catfish's developmental plasticity and its capacity to adapt its morphology and function to its environment. Through the comprehensive analysis of its genomic characteristics, it was found that the African sharptooth catfish has developed a series of unique respiratory adaptive mechanisms during the evolutionary process, These results not only advances the understanding of genetic adaptations to hypoxia in Clarias fish but also provides a valuable framework for future studies aimed at improving aquaculture practices,besides provide important references and inspirations for the evolution of aquatic organisms.
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Affiliation(s)
- Feiran Zhang
- Jiangsu Key Laboratory of Phylogenomics and Comparative Genomics, School of Life Sciences, Jiangsu Normal University, Xuzhou 221000, China
| | - Wenjing Wan
- Jiangsu Key Laboratory of Phylogenomics and Comparative Genomics, School of Life Sciences, Jiangsu Normal University, Xuzhou 221000, China
| | - Yang Li
- Jiangsu Key Laboratory of Phylogenomics and Comparative Genomics, School of Life Sciences, Jiangsu Normal University, Xuzhou 221000, China
| | - Bo Wang
- Jiangsu Key Laboratory of Phylogenomics and Comparative Genomics, School of Life Sciences, Jiangsu Normal University, Xuzhou 221000, China
| | - Yiting Shao
- Jiangsu Key Laboratory of Phylogenomics and Comparative Genomics, School of Life Sciences, Jiangsu Normal University, Xuzhou 221000, China
| | - Xiangyi Di
- Jiangsu Key Laboratory of Phylogenomics and Comparative Genomics, School of Life Sciences, Jiangsu Normal University, Xuzhou 221000, China
| | - Han Zhang
- Jiangsu Key Laboratory of Phylogenomics and Comparative Genomics, School of Life Sciences, Jiangsu Normal University, Xuzhou 221000, China
| | - Wenlong Cai
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong, China
| | - Yiliang Wei
- Jiangsu Key Laboratory of Phylogenomics and Comparative Genomics, School of Life Sciences, Jiangsu Normal University, Xuzhou 221000, China.
| | - Xiaoli Ma
- Jiangsu Key Laboratory of Phylogenomics and Comparative Genomics, School of Life Sciences, Jiangsu Normal University, Xuzhou 221000, China.
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5
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Agrawal A, Vindal V. Competing endogenous RNAs in head and neck squamous cell carcinoma: a review. Brief Funct Genomics 2024; 23:335-348. [PMID: 37941447 DOI: 10.1093/bfgp/elad049] [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: 07/25/2023] [Revised: 10/19/2023] [Accepted: 10/20/2023] [Indexed: 11/10/2023] Open
Abstract
Our understanding of RNA biology has evolved with recent advances in research from it being a non-functional product to molecules of the genome with specific regulatory functions. Competitive endogenous RNA (ceRNA), which has gained prominence over time as an essential part of post-transcriptional regulatory mechanism, is one such example. The ceRNA biology hypothesis states that coding RNA and non-coding RNA co-regulate each other using microRNA (miRNA) response elements. The ceRNA components include long non-coding RNAs, pseudogene and circular RNAs that exert their effect by interacting with miRNA and regulate the expression level of its target genes. Emerging evidence has revealed that the dysregulation of the ceRNA network is attributed to the pathogenesis of various cancers, including the head and neck squamous cell carcinoma (HNSCC). This is the most prevalent cancer developed from the mucosal epithelium in the lip, oral cavity, larynx and pharynx. Although many efforts have been made to comprehend the cause and subsequent treatment of HNSCC, the morbidity and mortality rate remains high. Hence, there is an urgent need to understand the holistic progression of HNSCC, mediated by ceRNA, that can have immense relevance in identifying novel biomarkers with a defined therapeutic intervention. In this review, we have made an effort to highlight the ceRNA biology hypothesis with a focus on its involvement in the progression of HNSCC. For the identification of such ceRNAs, we have additionally highlighted a number of databases and tools.
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Affiliation(s)
- Avantika Agrawal
- Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana 500046, India
| | - Vaibhav Vindal
- Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana 500046, India
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Hannon Bozorgmehr J. Four classic "de novo" genes all have plausible homologs and likely evolved from retro-duplicated or pseudogenic sequences. Mol Genet Genomics 2024; 299:6. [PMID: 38315248 DOI: 10.1007/s00438-023-02090-6] [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: 05/27/2023] [Accepted: 10/15/2023] [Indexed: 02/07/2024]
Abstract
Despite being previously regarded as extremely unlikely, the idea that entirely novel protein-coding genes can emerge from non-coding sequences has gradually become accepted over the past two decades. Examples of "de novo origination", resulting in lineage-specific "orphan" genes, lacking coding orthologs, are now produced every year. However, many are likely cases of duplicates that are difficult to recognize. Here, I re-examine the claims and show that four very well-known examples of genes alleged to have emerged completely "from scratch"- FLJ33706 in humans, Goddard in fruit flies, BSC4 in baker's yeast and AFGP2 in codfish-may have plausible evolutionary ancestors in pre-existing genes. The first two are likely highly diverged retrogenes coding for regulatory proteins that have been misidentified as orphans. The antifreeze glycoprotein, moreover, may not have evolved from repetitive non-genic sequences but, as in several other related cases, from an apolipoprotein that could have become pseudogenized before later being reactivated. These findings detract from various claims made about de novo gene birth and show there has been a tendency not to invest the necessary effort in searching for homologs outside of a very limited syntenic or phylostratigraphic methodology. A robust approach is used for improving detection that draws upon similarities, not just in terms of statistical sequence analysis, but also relating to biochemistry and function, to obviate notable failures to identify homologs.
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7
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Karimi B, Mokhtari K, Rozbahani H, Peymani M, Nabavi N, Entezari M, Rashidi M, Taheriazam A, Ghaedi K, Hashemi M. Pathological roles of miRNAs and pseudogene-derived lncRNAs in human cancers, and their comparison as prognosis/diagnosis biomarkers. Pathol Res Pract 2024; 253:155014. [PMID: 38128189 DOI: 10.1016/j.prp.2023.155014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/02/2023] [Accepted: 12/02/2023] [Indexed: 12/23/2023]
Abstract
This review examines and compares the diagnostic and prognostic capabilities of miRNAs and lncRNAs derived from pseudogenes in cancer patients. Additionally, it delves into their roles in cancer pathogenesis. Both miRNAs and pseudogene-derived lncRNAs have undergone thorough investigation as remarkably sensitive and specific cancer biomarkers, offering significant potential for cancer detection and monitoring. . Extensive research is essential to gain a complete understanding of the precise roles these non-coding RNAs play in cancer, allowing the development of novel targeted therapies and biomarkers for improved cancer detection and treatment approaches.
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Affiliation(s)
- Bahareh Karimi
- Department of Cellular and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Khatere Mokhtari
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Hossein Rozbahani
- Department of Psychology, North Tehran Branch, Islamic Azad University, Tehran, Iran; Department of Psychology, West Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H3Z6, Canada
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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8
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Yadav S, Kalwan G, Meena S, Gill SS, Yadava YK, Gaikwad K, Jain PK. Unravelling the due importance of pseudogenes and their resurrection in plants. PLANT PHYSIOLOGY AND BIOCHEMISTRY : PPB 2023; 203:108062. [PMID: 37778114 DOI: 10.1016/j.plaphy.2023.108062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/22/2023] [Accepted: 09/26/2023] [Indexed: 10/03/2023]
Abstract
The complexities of a genome are underpinned to the vast expanses of the intergenic region, which constitutes ∼97-98% of the genome. This region is essentially composed of what is colloquially referred to as the "junk DNA" and is composed of various elements like transposons, repeats, pseudogenes, etc. The latter have long been considered as dead elements merely contributing to transcriptional noise in the genome. Many studies now describe the previously unknown regulatory functions of these genes. Recent advances in the Next-generation sequencing (NGS) technologies have allowed unprecedented access to these regions. With the availability of whole genome sequences of more than 788 different plant species in past 20 years, genome annotation has become feasible like never before. Different bioinformatic pipelines are available for the identification of pseudogenes. However, still little is known about their biological functions. The functional validation of these genes remains challenging and research in this area is still in infancy, particularly in plants. CRISPR/Cas-based genome editing could provide solutions to understand the biological roles of these genes by allowing creation of precise edits within these genes. The possibility of pseudogene reactivation or resurrection as has been demonstrated in a few studies might open new avenues of genetic manipulation to yield a desirable phenotype. This review aims at comprehensively summarizing the progress made with regards to the identification of pseudogenes and understanding their biological functions in plants.
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Affiliation(s)
- Sheel Yadav
- ICAR-National Institute for Plant Biotechnology, New Delhi, 110012, India; PG School, ICAR-Indian Agricultural Research Institute, New Delhi, 110012, India; Division of Genomic Resources, ICAR-National Bureau of Plant Genetic Resources, New Delhi, 110012, India
| | - Gopal Kalwan
- ICAR-National Institute for Plant Biotechnology, New Delhi, 110012, India; PG School, ICAR-Indian Agricultural Research Institute, New Delhi, 110012, India
| | - Shashi Meena
- PG School, ICAR-Indian Agricultural Research Institute, New Delhi, 110012, India; Division of Plant Physiology, ICAR-Indian Agricultural Research Institute, New Delhi, 110012, India
| | - Sarvajeet Singh Gill
- Stress Physiology & Molecular Biology Lab, Centre for Biotechnology, Maharshi Dayanand University, Rohtak, 124 001, Haryana, India
| | - Yashwant K Yadava
- ICAR-National Institute for Plant Biotechnology, New Delhi, 110012, India
| | - Kishor Gaikwad
- ICAR-National Institute for Plant Biotechnology, New Delhi, 110012, India
| | - P K Jain
- ICAR-National Institute for Plant Biotechnology, New Delhi, 110012, India.
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9
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Meng W, Johnsen KM, Fenton CG, Florholmen J, Paulssen RH. Anti-apoptotic genes and non-coding RNAs are potential outcome predictors for ulcerative colitis. Funct Integr Genomics 2023; 23:165. [PMID: 37199828 DOI: 10.1007/s10142-023-01099-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 05/10/2023] [Accepted: 05/11/2023] [Indexed: 05/19/2023]
Abstract
Due to the lack of clinical, immunologic, genetic, and laboratory markers to predict remission in ulcerative colitis (UC) without relapse, there is no clear recommendation regarding withdrawal of therapy. Therefore, this study was to investigate if transcriptional analysis together with Cox survival analysis might be able to reveal molecular markers that are specific for remission duration and outcome. Mucosal biopsies from patients in remission with active treatment-naïve UC and healthy control subjects underwent whole-transcriptome RNA-seq. Principal component analysis (PCA) and Cox proportional hazards regression analysis were applied to the remission data concerning duration and status of patients. A randomly chosen remission sample set was used for validation of the applied methods and results. The analyses distinguished two different UC remission patient groups with respect to remission duration and outcome (relapse). Both groups showed that altered states of UC with quiescent microscopic disease activity are still present. The patient group with the longest remission duration and no relapse revealed specific and increased expression of antiapoptotic factors belonging to the MTRNR2-like gene family and non-coding RNAs. In summary, the expression of anti-apoptotic factors and non-coding RNAs may contribute to personalized medicine approaches in UC by improving patient stratification for different treatment regimens.
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Affiliation(s)
- Wei Meng
- Clinical Bioinformatics Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT- The Arctic University of Norway, Tromsø, Norway
| | - Kay-Martin Johnsen
- Gastroenterology and Nutrition Research Group, Faculty of Health Sciences, UiT- The Arctic University of Norway, Tromsø, Norway
- Department of Medical Gastroenterology, University Hospital of North Norway, Tromsø, Norway
| | - Christopher G Fenton
- Genomics Support Centre Tromsø, UiT- The Arctic University of Norway, Department of Clinical Medicine, Faculty of Health Sciences, UiT- The Arctic University of Norway, Sykehusveien 44, N-9037, Tromsø, Norway
| | - Jon Florholmen
- Gastroenterology and Nutrition Research Group, Faculty of Health Sciences, UiT- The Arctic University of Norway, Tromsø, Norway
| | - Ruth H Paulssen
- Clinical Bioinformatics Research Group, Department of Clinical Medicine, Faculty of Health Sciences, UiT- The Arctic University of Norway, Tromsø, Norway.
- Genomics Support Centre Tromsø, UiT- The Arctic University of Norway, Department of Clinical Medicine, Faculty of Health Sciences, UiT- The Arctic University of Norway, Sykehusveien 44, N-9037, Tromsø, Norway.
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Kumar R, Mondal R, Lahiri T, Pal MK. Application of sequence semantic and integrated cellular geography approach to study alternative biogenesis of exonic circular RNA. BMC Bioinformatics 2023; 24:148. [PMID: 37069509 PMCID: PMC10108499 DOI: 10.1186/s12859-023-05279-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/09/2023] [Indexed: 04/19/2023] Open
Abstract
BACKGROUND Concurrent existence of lncRNA and circular RNA at both nucleus and cytosol within a cell at different proportions is well reported. Previous studies showed that circular RNAs are synthesized in nucleus followed by transportation across the nuclear membrane and the export is primarily defined by their length. lncRNAs primarily originated through inefficient splicing and seem to use NXF1 for cytoplasm export. However, it is not clear whether circularization of lncRNA happens only in nucleus or it also occurs in cytoplasm. Studies indicate that circular RNAs arise when the splicing apparatus undergoes a phenomenon of back splicing. Minor spliceosome (U12 type) mediated splicing occurs in cytoplasm and is responsible for the splicing of 0.5% of introns of human cells. Therefore, possibility of cRNA biogenesis mediated by minor spliceosome at cytoplasm cannot be ruled out. Secondly, information on genes transcribing both circular and lncRNAs along with total number of RBP binding sites for both of these RNA types is extractable from databases. This study showed how these apparently unconnected pieces of reports could be put together to build a model for exploring biogenesis of circular RNA. RESULTS As a result of this study, a model was built under the premises that, sequences with special semantics were molecular precursors in biogenesis of circular RNA which occurred through catalytic role of some specific RBPs. The model outcome was further strengthened by fulfillment of three logical lemmas which were extracted and assimilated in this work using a novel data analytic approach, Integrated Cellular Geography. Result of the study was found to be in well agreement with proposed model. Furthermore this study also indicated that biogenesis of circular RNA was a post-transcriptional event. CONCLUSIONS Overall, this study provides a novel systems biology based model under the paradigm of Integrated Cellular Geography which can assimilate independently performed experimental results and data published by global researchers on RNA biology to provide important information on biogenesis of circular RNAs considering lncRNAs as precursor molecule. This study also suggests the possible RBP-mediated circularization of RNA in the cytoplasm through back-splicing using minor spliceosome.
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Affiliation(s)
- Rajnish Kumar
- Department of Pathology and Laboratory Medicine, Medical Center, University of Kansas, Kansas City, 66160, USA
| | - Rajkrishna Mondal
- Department of Biotechnology, Nagaland University, Dimapur, Nagaland, 797112, India
| | - Tapobrata Lahiri
- Room No. 4302, Department of Applied Sciences, Computer Centre - II, Indian Institute of Information Technology-Allahabad, Allahabad, 211015, India.
| | - Manoj Kumar Pal
- Faculty of Engineering and Technology, United University Prayagraj, Prayagraj, UP, 211012, India
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11
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Protein-Coding Region Derived Small RNA in Exosomes from Influenza A Virus-Infected Cells. Int J Mol Sci 2023; 24:ijms24010867. [PMID: 36614310 PMCID: PMC9820831 DOI: 10.3390/ijms24010867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/28/2022] [Accepted: 12/30/2022] [Indexed: 01/05/2023] Open
Abstract
Exosomes may function as multifactorial mediators of cell-to-cell communication, playing crucial roles in both physiological and pathological processes. Exosomes released from virus-infected cells may contain RNA and proteins facilitating infection spread. The purpose of our study was to analyze how the small RNA content of exosomes is affected by infection with the influenza A virus (IAV). Exosomes were isolated by ultracentrifugation after hemadsorption of virions and their small RNA content was identified using high-throughput sequencing. As compared to mock-infected controls, 856 RNA transcripts were significantly differentially expressed in exosomes from IAV-infected cells, including fragments of 458 protein-coding (pcRNA), 336 small, 28 long intergenic non-coding RNA transcripts, and 33 pseudogene transcripts. Upregulated pcRNA species corresponded mainly to proteins associated with translation and antiviral response, and the most upregulated among them were RSAD2, CCDC141 and IFIT2. Downregulated pcRNA species corresponded to proteins associated with the cell cycle and DNA packaging. Analysis of differentially expressed pseudogenes showed that in most cases, an increase in the transcription level of pseudogenes was correlated with an increase in their parental genes. Although the role of exosome RNA in IAV infection remains undefined, the biological processes identified based on the corresponding proteins may indicate the roles of some of its parts in IAV replication.
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12
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Paul KC, Kusters C, Furlong M, Zhang K, Yu Y, Folle AD, Del Rosario I, Keener A, Bronstein J, Sinsheimer JS, Horvath S, Ritz B. Immune system disruptions implicated in whole blood epigenome-wide association study of depression among Parkinson's disease patients. Brain Behav Immun Health 2022; 26:100530. [PMID: 36325427 PMCID: PMC9618774 DOI: 10.1016/j.bbih.2022.100530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 10/01/2022] [Indexed: 11/09/2022] Open
Abstract
Although Parkinson's Disease (PD) is typically described in terms of motor symptoms, depression is a common feature. We explored whether depression influences blood-based genome-wide DNA methylation (DNAm) in 692 subjects from a population-based PD case-control study, using both a history of clinically diagnosed depression and current depressive symptoms measured by the geriatric depression scale (GDS). While PD patients in general had more immune activation and more accelerated epigenetic immune system aging than controls, the patients experiencing current depressive symptoms (GDS≥5) showed even higher levels of both markers than patients without current depressive symptoms (GDS<5). For PD patients with a history of clinical depression compared to those without, we found no differences in immune cell composition. However, a history of clinical depression among patients was associated with differentially methylated CpGs. Epigenome-wide association analysis (EWAS) revealed 35 CpGs associated at an FDR≤0.05 (569 CpGs at FDR≤0.10, 1718 CpGs at FDR≤0.15). Gene set enrichment analysis implicated immune system pathways, including immunoregulatory interactions between lymphoid and non-lymphoid cells (p-adj = 0.003) and cytokine-cytokine receptor interaction (p-adj = 0.004). Based on functional genomics, 25 (71%) of the FDR≤0.05 CpGs were associated with genetic variation at 45 different methylation quantitative trait loci (meQTL). Twenty-six of the meQTLs were also expression QTLs (eQTLs) associated with the abundance of 53 transcripts in blood and 22 transcripts in brain (substantia nigra, putamen basal ganglia, or frontal cortex). Notably, cg15199181 was strongly related to rs823114 (SNP-CpG p-value = 3.27E-310), a SNP identified in a PD meta-GWAS and related to differential expression of PM20D1, RAB29, SLC41A1, and NUCKS1. The entire set of genes detected through functional genomics was most strongly overrepresented for interferon-gamma-mediated signaling pathway (enrichment ratio = 18.8, FDR = 4.4e-03) and T cell receptor signaling pathway (enrichment ratio = 13.2, FDR = 4.4e-03). Overall, the current study provides evidence of immune system involvement in depression among Parkinson's patients.
Parkinson's disease (PD) is associated with clinical depression prior to PD onset and depressive symptoms after PD diagnosis. Epigenome-wide analysis revealed CpGs related to current depressive symptoms and a history of clinical depression among PD patients. Patients experiencing current depressive symptoms had the highest epigenetic-based neutrophil-to-lymphocyte ratio on average. Patients with a history of clinical depression had differentially methylated CpGs in genes enriched for immune system pathways. Many of the depression associated CpGs were linked to differential expression through meQTL/eQTLs, which included GWAS variants.
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Affiliation(s)
- Kimberly C. Paul
- Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA
- Corresponding author. 73-320B CHS, CAMPUS-177220, UCLA, Los Angeles, CA, 90095, USA.
| | - Cynthia Kusters
- Departments of Human Genetics, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Melissa Furlong
- University of Arizona, Mel and Enid Zuckerman College of Public Health, Tucson, AZ, USA
| | - Keren Zhang
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA
| | - Yu Yu
- Center for Health Policy Research, UCLA Fielding School of Public Health, Los Angeles, CA, USA
| | - Aline Duarte Folle
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA
| | - Irish Del Rosario
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA
| | - Adrienne Keener
- Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Jeff Bronstein
- Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Janet S. Sinsheimer
- Departments of Human Genetics, David Geffen School of Medicine, Los Angeles, CA, USA
- Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA, USA
| | - Steve Horvath
- Departments of Human Genetics, David Geffen School of Medicine, Los Angeles, CA, USA
- Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA, USA
| | - Beate Ritz
- Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, USA
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA
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13
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Vihinen M. Individual Genetic Heterogeneity. Genes (Basel) 2022; 13:1626. [PMID: 36140794 PMCID: PMC9498725 DOI: 10.3390/genes13091626] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 08/25/2022] [Accepted: 09/08/2022] [Indexed: 11/28/2022] Open
Abstract
Genetic variation has been widely covered in literature, however, not from the perspective of an individual in any species. Here, a synthesis of genetic concepts and variations relevant for individual genetic constitution is provided. All the different levels of genetic information and variation are covered, ranging from whether an organism is unmixed or hybrid, has variations in genome, chromosomes, and more locally in DNA regions, to epigenetic variants or alterations in selfish genetic elements. Genetic constitution and heterogeneity of microbiota are highly relevant for health and wellbeing of an individual. Mutation rates vary widely for variation types, e.g., due to the sequence context. Genetic information guides numerous aspects in organisms. Types of inheritance, whether Mendelian or non-Mendelian, zygosity, sexual reproduction, and sex determination are covered. Functions of DNA and functional effects of variations are introduced, along with mechanism that reduce and modulate functional effects, including TARAR countermeasures and intraindividual genetic conflict. TARAR countermeasures for tolerance, avoidance, repair, attenuation, and resistance are essential for life, integrity of genetic information, and gene expression. The genetic composition, effects of variations, and their expression are considered also in diseases and personalized medicine. The text synthesizes knowledge and insight on individual genetic heterogeneity and organizes and systematizes the central concepts.
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Affiliation(s)
- Mauno Vihinen
- Department of Experimental Medical Science, BMC B13, Lund University, SE-22184 Lund, Sweden
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14
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Wei B, Liu Y, Li H, Peng Y, Luo Z. Effect of 9p21.3 (lncRNA and CDKN2A/2B) variant on lipid profile. Front Cardiovasc Med 2022; 9:946289. [PMID: 36158791 PMCID: PMC9489913 DOI: 10.3389/fcvm.2022.946289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 08/16/2022] [Indexed: 11/17/2022] Open
Abstract
Background Several 9p21.3 variants, such as rs1333049, rs4977574, rs10757274, rs10757278, and rs10811661, identified from recent genome-wide association studies (GWASs) are reported to be associated with coronary artery disease (CAD) susceptibility but independent of dyslipidemia. This study investigated whether these 9p21.3 variants influenced lipid profiles. Methods and results By searching the PubMed and Cochrane databases, 101,099 individuals were included in the analysis. The consistent finding for the rs1333049 C allele on lipid profiles increased the triglyceride (TG) levels. Moreover, the rs4977574 G allele and the rs10757274 G allele, respectively, increased low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels. However, the rs10811661 C allele largely reduced LDL-C levels. Subgroup analyses indicated that the effects of the rs1333049 C allele, rs4977574 G allele, and rs10757274 G allele on lipid profiles were stronger in Whites compared with Asians. In contrast, the effect of the rs10811661 C allele on lipid profiles was stronger in Asians compared with Whites. Conclusion The rs1333049 C allele, rs4977574 G allele, and rs10757274 G allele of lncRNA, and the rs10811661 G allele of CDKN2A/2B had a significant influence on lipid levels, which may help the understanding of the underlying mechanisms between 9p21.3 variants and CAD.
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Affiliation(s)
- Baozhu Wei
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
- Institute of Myocardial Injury and Repair, Wuhan University, Wuhan, China
- *Correspondence: Baozhu Wei,
| | - Yang Liu
- Department of Endocrinology, China Resources and WISCO General Hospital, Wuhan, China
| | - Hang Li
- Department of Gerontology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yuanyuan Peng
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Zhi Luo
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
- Zhi Luo,
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15
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Choo SW, Zhong Y, Sendler E, Goustin AS, Cai J, Ju D, Kosir MA, Giordo R, Lipovich L. Estrogen distinctly regulates transcription and translation of lncRNAs and pseudogenes in breast cancer cells. Genomics 2022; 114:110421. [PMID: 35779786 DOI: 10.1016/j.ygeno.2022.110421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 05/25/2022] [Accepted: 06/25/2022] [Indexed: 11/04/2022]
Abstract
Estrogen drives key transcriptional changes in breast cancer and stimulates breast cancer cells' growth with multiple mechanisms to coordinate transcription and translation. In addition to protein-coding transcripts, estrogen can regulate long non-coding RNA (lncRNA) transcripts, plus diverse non-coding RNAs including antisense, enhancer, and intergenic. LncRNA genes comprise the majority of human genes. The accidental, or regulated, translation of their short open reading frames by ribosomes remains a controversial topic. Here we report for the first time an integrated analysis of RNA abundance and ribosome occupancy level, using Ribo-seq combined with RNA-Seq, in the estrogen-responsive, estrogen receptor α positive, human breast cancer cell model MCF7, before and after hormone treatment. Translational profiling can determine, in an unbiased manner, which fraction of the genome is actually translated into proteins, as well as resolving whether transcription and translation respond concurrently, or differentially, to estrogen treatment. Our data showed specific transcripts more robustly detected in RNA-Seq than in the ribosome-profiling data, and vice versa, suggesting distinct gene-specific estrogen responses at the transcriptional and the translational level, respectively. Here, we showed that estrogen stimulation affects the expression levels of numerous lncRNAs, but not their association with ribosomes, and that most lncRNAs are not ribosome-bound. For the first time, we also demonstrated the transcriptional and translational response of expressed pseudogenes to estrogen, pointing to new perspectives for drug-target development in breast cancer in the future.
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Affiliation(s)
- Siew-Woh Choo
- Department of Biology, College of Science and Technology, Wenzhou-Kean University, 88 Daxue Road, Ouhai, Wenzhou, Zhejiang Province, China; Zhejiang Bioinformatics International Science and Technology Cooperation Center, Ouhai, Wenzhou, Zhejiang Province, China; Wenzhou Municipal Key Laboratory for Applied Biomedical and Biopharmaceutical Informatics, Ouhai, Wenzhou, Zhejiang Province, China.
| | - Yu Zhong
- Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Edward Sendler
- Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, USA
| | - Anton-Scott Goustin
- Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, USA
| | - Juan Cai
- Department of Biochemistry, Microbiology and Immunology School of Medicine, Wayne State University, Detroit, USA
| | - Donghong Ju
- Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, USA; Department of Surgery and Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, USA
| | - Mary Ann Kosir
- Department of Surgery and Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, USA
| | - Roberta Giordo
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates.
| | - Leonard Lipovich
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates.
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16
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LINC01535 Attenuates ccRCC Progression through Regulation of the miR-146b-5p/TRIM2 Axis and Inactivation of the PI3K/Akt Pathway. JOURNAL OF ONCOLOGY 2022; 2022:2153337. [PMID: 35342411 PMCID: PMC8947867 DOI: 10.1155/2022/2153337] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/17/2022] [Accepted: 02/24/2022] [Indexed: 01/09/2023]
Abstract
lncRNAs, a group of eukaryotic cell genome-encoded transcripts, have been demonstrated to exert a notable impact on tumorigenesis. LINC01535, belonging to the lncRNA family, was reported to have an aberrant expression in certain types of cancers and thus affect cancer progression. Nevertheless, the expression pattern and potential roles of LINC01535 in clear cell renal cell carcinoma (ccRCC) remain to be elucidated. Here, LINC01535 expression was detected in ccRCC by RT-qPCR, cell proliferation by CCK-8 assays, and invasion by transwell assays. Besides, effects of LINC01535 on in vivo tumor growth were investigated by xenograft tumor models. The miR-146b-5p/LINC01535/TRIM2 interaction was evaluated via luciferase reporter assays. This study showed downregulation of LINC01535 in ccRCC. Moreover, LINC01535 upregulation attenuated in vitro ccRCC development and hindered in vivo tumor growth. Furthermore, LINC01535 sponged miR-146b-5p which had a negative correlation with LINC01535, and TRIM2 was a direct target of miR-146b-5p and mediated by LINC01535. Mechanically, LINC01535/miR-146b-5p/TRIM2 axis affected ccRCC progression by mediating the PI3K/Akt signaling. All in all, our observations suggest the LINC01535/miR-146b-5p/TRIM2 axis as a crucial role in ccRCC.
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17
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Guo M, Zhang X. LncRNA MSTO2P promotes colorectal cancer progression through epigenetically silencing CDKN1A mediated by EZH2. World J Surg Oncol 2022; 20:95. [PMID: 35346226 PMCID: PMC8961944 DOI: 10.1186/s12957-022-02567-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/15/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Pseudogene-derived long non-coding RNAs (lncRNAs) have been reported to act as key regulatory factors of cancers. However, the study focused on pseudogene misato family member 2 (MSTO2P) in the occurrence and development of colorectal cancer (CRC) remains unclear. METHODS CCK-8, colony formation, and transwell assays clarified HT-29 and SW480 cell proliferation and invasion. Furthermore, flow cytometry was carried out to detect cell cycle and cell apoptosis. Subcellular localization assay indicated the location of MSTO2P in HT-29 cells. RIP and CHIP assays clarified the relationship of MSTO2P with target protein and gene in HT-29 cells. RESULTS MSTO2P expression was upregulated in CRC tissues and cells. Functional experiments revealed that inhibition of MSTO2P suppressed HT-29 and SW480 cell proliferation and invasion, and promoted cell cycle arrest and cell apoptosis. Besides, MSTO2P epigenetically down-regulated cyclin-dependent kinase inhibitor 1A (CDKN1A) via binding to the enhancer of zeste homolog 2 (EZH2) in the nucleus. At last, rescue experiments proved the anti-tumor effect of inhibition of MSTO2P was partially recovered due to the knockdown of CDKN1A in HT-29 cells. CONCLUSION LncRNA MSTO2P promoted colorectal cancer progression through epigenetically silencing CDKN1A mediated by EZH2.
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Affiliation(s)
- Mengjun Guo
- Department of Anus and Intestine Surgery, Shaanxi Provincial People's Hospital, West Youyi Road, Xi'an, 710000, Shaanxi, China
| | - Xiling Zhang
- Department of Anus and Intestine Surgery, Shaanxi Provincial People's Hospital, West Youyi Road, Xi'an, 710000, Shaanxi, China.
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18
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Opazo JC, Zavala K, Vargas-Chacoff L, Morera FJ, Mardones GA. Identification of multiple TAR DNA binding protein retropseudogene lineages during the evolution of primates. Sci Rep 2022; 12:3823. [PMID: 35264686 PMCID: PMC8907276 DOI: 10.1038/s41598-022-07908-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 02/22/2022] [Indexed: 11/08/2022] Open
Abstract
The TAR DNA Binding Protein (TARDBP) gene has become relevant after the discovery of its several pathogenic mutations. The lack of evolutionary history is in contrast to the amount of studies found in the literature. This study investigated the evolutionary dynamics associated with the retrotransposition of the TARDBP gene in primates. We identified novel retropseudogenes that likely originated in the ancestors of anthropoids, catarrhines, and lemuriformes, i.e. the strepsirrhine clade that inhabit Madagascar. We also found species-specific retropseudogenes in the Philippine tarsier, Bolivian squirrel monkey, capuchin monkey and vervet. The identification of a retropseudocopy of the TARDBP gene overlapping a lncRNA that is potentially expressed opens a new avenue to investigate TARDBP gene regulation, especially in the context of TARDBP associated pathologies.
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Affiliation(s)
- Juan C Opazo
- Integrative Biology Group, Universidad Austral de Chile, Valdivia, Chile.
- Instituto de Ciencias Ambientales y Evolutivas, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile.
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Valdivia, Chile.
| | - Kattina Zavala
- Instituto de Ciencias Ambientales y Evolutivas, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Luis Vargas-Chacoff
- Integrative Biology Group, Universidad Austral de Chile, Valdivia, Chile
- Instituto de Ciencias Marinas y Limnológicas, Universidad Austral de Chile, Valdivia, Chile
- Centro Fondap de Investigación de Altas Latitudes (IDEAL), Universidad Austral de Chile, Valdivia, Chile
| | - Francisco J Morera
- Integrative Biology Group, Universidad Austral de Chile, Valdivia, Chile
- Applied Biochemistry Laboratory, Facultad de Ciencias Veterinarias, Instituto de Farmacología y Morfofisiología, Universidad Austral de Chile, Valdivia, Chile
| | - Gonzalo A Mardones
- Integrative Biology Group, Universidad Austral de Chile, Valdivia, Chile.
- Department of Physiology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
- Center for Interdisciplinary Studies of the Nervous System (CISNe), Universidad Austral de Chile, Valdivia, Chile.
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Ilieva M, Uchida S. Long Non-Coding RNAs in Induced Pluripotent Stem Cells and Their Differentiation. Am J Physiol Cell Physiol 2022; 322:C769-C774. [PMID: 35235428 DOI: 10.1152/ajpcell.00059.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The breakthrough technology for reprogramming somatic cells into induced pluripotent stem cells (iPSC) has created a new path for science and medicine. The iPSC technology provides a powerful tool for elucidating the mechanisms of cellular differentiation and cell fate decision as well as to study targets and pathways relevant to pathological processes. Since they can be generated from any person, iPSC are a promising resource for regenerative medicine potentiating the possibility to discover new drugs in a high-throughput screening format and treat diseases through personalized cell therapy-based strategies. However, the reprogramming process is complex, and its regulation needs fine tuning. The regulatory mechanisms of cell reprogramming and differentiation are still not elucidated, but significant results show that multiple long non-coding RNAs (lncRNAs) play essential roles. In this mini review, we discuss the latest research on lncRNAs in iPSC stemness, neuronal and cardiac differentiation.
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Affiliation(s)
- Mirolyuba Ilieva
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen SV, Denmark
| | - Shizuka Uchida
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen SV, Denmark
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20
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Alvarado-Hernandez B, Ma Y, Sharma NR, Majerciak V, Lobanov A, Cam M, Zhu J, Zheng ZM. Protein-RNA Interactome Analysis Reveals Wide Association of Kaposi's Sarcoma-Associated Herpesvirus ORF57 with Host Noncoding RNAs and Polysomes. J Virol 2022; 96:e0178221. [PMID: 34787459 PMCID: PMC8826805 DOI: 10.1128/jvi.01782-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 11/07/2021] [Indexed: 12/15/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 is an RNA-binding posttranscriptional regulator. We recently applied an affinity-purified anti-ORF57 antibody to conduct ORF57 cross-linking immunoprecipitation (CLIP) in combination with RNA-sequencing (CLIP-seq) and analyzed the genome-wide host RNA transcripts in association with ORF57 in BCBL-1 cells with lytic KSHV infection. Mapping of the CLIP RNA reads to the human genome (GRCh37) revealed that most of the ORF57-associated RNA reads were from rRNAs. The remaining RNA reads mapped to several classes of host noncoding and protein-coding mRNAs. We found that ORF57 binds and regulates expression of a subset of host long noncoding RNAs (lncRNAs), including LINC00324, LINC00355, and LINC00839, which are involved in cell growth. ORF57 binds small nucleolar RNAs (snoRNAs) responsible for 18S and 28S rRNA modifications but does not interact with fibrillarin or NOP58. We validated ORF57 interactions with 67 snoRNAs by ORF57 RNA immunoprecipitation (RIP)-snoRNA array assays. Most of the identified ORF57 rRNA binding sites (BS) overlap the sites binding snoRNAs. We confirmed ORF57-snoRA71B RNA interaction in BCBL-1 cells by ORF57 RIP and Northern blot analyses using a 32P-labeled oligonucleotide probe from the 18S rRNA region complementary to snoRA71B. Using RNA oligonucleotides from the rRNA regions that ORF57 binds for oligonucleotide pulldown-Western blot assays, we selectively verified ORF57 interactions with 5.8S and 18S rRNAs. Polysome profiling revealed that ORF57 associates with both monosomes and polysomes and that its association with polysomes increases PABPC1 binding to polysomes but prevents Ago2 association with polysomes. Our data indicate a functional correlation with ORF57 binding and suppression of Ago2 activities for ORF57 promotion of gene expression. IMPORTANCE As an RNA-binding protein, KSHV ORF57 regulates RNA splicing, stability, and translation and inhibits host innate immunity by blocking the formation of RNA granules in virus-infected cells. In this study, ORF57 was found to interact with many host noncoding RNAs, including lncRNAs, snoRNAs, and rRNAs, to carry out additional unknown functions. ORF57 binds a group of lncRNAs via the RNA motifs identified by ORF57 CLIP-seq to regulate their expression. ORF57 associates with snoRNAs independently of fibrillarin and NOP58 proteins and with rRNA in the regions that commonly bind snoRNAs. Knockdown of fibrillarin expression decreases the expression of snoRNAs and CDK4 but does not affect viral gene expression. More importantly, we found that ORF57 binds translationally active polysomes and enhances PABPC1 but prevents Ago2 association with polysomes. Data provide compelling evidence on how ORF57 in KSHV-infected cells might regulate protein synthesis by blocking Ago2's hostile activities on translation.
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Affiliation(s)
- Beatriz Alvarado-Hernandez
- Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI/NIH, Frederick, Maryland, USA
| | - Yanping Ma
- Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI/NIH, Frederick, Maryland, USA
| | - Nishi R. Sharma
- Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI/NIH, Frederick, Maryland, USA
| | - Vladimir Majerciak
- Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI/NIH, Frederick, Maryland, USA
| | - Alexei Lobanov
- CCR Collaborative Bioinformatics Resource, Center for Cancer Research, NCI/NIH, Bethesda, Maryland, USA
| | - Maggie Cam
- CCR Collaborative Bioinformatics Resource, Center for Cancer Research, NCI/NIH, Bethesda, Maryland, USA
| | - Jun Zhu
- Genome Technology Laboratory, System Biology Center, NHLBI/NIH, Bethesda, Maryland, USA
| | - Zhi-Ming Zheng
- Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI/NIH, Frederick, Maryland, USA
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21
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Kim HC, Jolly ER. LncRNAs Are Differentially Expressed between Wildtype and Cell Line Strains of African Trypanosomes. Noncoding RNA 2022; 8:ncrna8010007. [PMID: 35076577 PMCID: PMC8788480 DOI: 10.3390/ncrna8010007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/02/2022] [Accepted: 01/08/2022] [Indexed: 12/15/2022] Open
Abstract
Trypanosoma brucei is a parasitic protist that causes African sleeping sickness. The establishment of T. brucei cell lines has provided a significant advantage for the majority of T. brucei research. However, these cell lines were isolated and maintained in culture for decades, occasionally accumulating changes in gene expression. Since trypanosome strains have been maintained in culture for decades, it is possible that difference may have accumulated in fast-evolving non-coding RNAs between trypanosomes from the wild and those maintained extensively in cultures. To address this, we compared the lncRNA expression profile of trypanosomes maintained as cultured cell lines (CL) to those extracted from human patients, wildtype (WT). We identified lncRNAs from CL and WT from available transcriptomic data and demonstrate that CL and WT have unique sets of lncRNAs expressed. We further demonstrate that the unique and shared lncRNAs are differentially expressed between CL and WT parasites, and that these lncRNAs are more evenly up-regulated and down-regulated than protein-coding genes. We validated the expression of these lncRNAs using qPCR. Taken together, this study demonstrates that lncRNAs are differentially expressed between cell lines and wildtype T. brucei and provides evidence for potential evolution of lncRNAs, specifically in T. brucei maintained in culture.
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Affiliation(s)
- Hyung Chul Kim
- Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA;
| | - Emmitt R. Jolly
- Department of Biology, Case Western Reserve University, Cleveland, OH 44106, USA;
- Center for Global Health and Disease, Case Western Reserve University, Cleveland, OH 44106, USA
- Center for RNA Science and Therapeutics, Case Western Reserve University, Cleveland, OH 44106, USA
- Correspondence:
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22
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Nair J, Maheshwari A. Non-coding RNAs in Necrotizing Enterocolitis- A New Frontier? Curr Pediatr Rev 2022; 18:25-32. [PMID: 34727861 DOI: 10.2174/1573396317666211102093646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 06/30/2021] [Accepted: 09/01/2021] [Indexed: 11/22/2022]
Abstract
With the recognition that only 2% of the human genome encodes for a protein, a large part of the "non-coding" portion is now being evaluated for a regulatory role in cellular processes. These non-coding RNAs (ncRNAs) are subdivided based on the size of the nucleotide transcript into microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), but most of our attention has been focused on the role of microRNAs (miRNAs) in human health and disease. Necrotizing enterocolitis (NEC), an inflammatory bowel necrosis affecting preterm infants, has a multifactorial, unclear etiopathogenesis, and we have no specific biomarkers for diagnosis or the impact of directed therapies. The information on ncRNAs, in general, and particularly in NEC, is limited. Increasing information from other inflammatory bowel disorders suggests that these transcripts may play an important role in intestinal inflammation. Here, we review ncRNAs for definitions, classifications, and possible roles in prematurity and NEC using some preliminary information from our studies and from an extensive literature search in multiple databases including PubMed, EMBASE, and Science Direct. miRNAs will be described in another manuscript in this series, hence in this manuscript we mainly focus on lncRNAs.
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Affiliation(s)
- Jayasree Nair
- Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Akhil Maheshwari
- Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA
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Ou H, Liu Q, Lin J, He W, Zhang W, Ma J, Wang W. Pseudogene Annexin A2 Pseudogene 1 Contributes to Hepatocellular Carcinoma Progression by Modulating Its Parental Gene ANXA2 via miRNA-376a-3p. Dig Dis Sci 2021; 66:3903-3915. [PMID: 33398718 DOI: 10.1007/s10620-020-06734-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 11/18/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Pseudogenes are defined as key regulators in cancer initiation and progression. But their biological function and clinical significance in hepatocellular carcinoma (HCC) remain to be elucidated. In the current study, we identified a novel pseudogene, Annexin A2 pseudogene 1 (ANXA2P1), in HCC and explored its underlining molecular mechanism. METHODS AND RESULTS We analyzed the expression pattern of ANXA2P1 in a TCGA dataset and an HCC sample cohort and evaluated its clinical significance. The biological effects on HCC cells proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process were assessed by Cell Counting Kit-8 assay, Transwell assay and Western blot, respectively. The ANXA2P1/miR-376a-3p/ANXA2 axis was determined by bioinformatics analysis and dual-luciferase reporter assays. ANXA2P1 exerted as an oncogene that was significantly overexpressed in HCC tissues and was associated with disease progression and unfavorable prognosis of HCC patients. ANXA2P1 knockdown suppressed cell growth, cell migration and invasion and reversed EMT phenotype in HCC. Mechanistically, ANXA2P1 acts as a competing endogenous RNA for miR-376a-3p, thereby leading to the upregulation of its cognate gene ANXA2. CONCLUSIONS ANXA2P1/miR-376a-3p/ANXA2 axis plays an important role in the progression of HCC. Our findings may provide valuable therapeutic target for treating HCC.
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Affiliation(s)
- Huohui Ou
- Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), No. 1 Jiazi Road, Lunjiao, Shunde District, Foshan, 528308, Guangdong Province, China
| | - Qingbo Liu
- Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), No. 1 Jiazi Road, Lunjiao, Shunde District, Foshan, 528308, Guangdong Province, China
| | - Jie Lin
- Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), No. 1 Jiazi Road, Lunjiao, Shunde District, Foshan, 528308, Guangdong Province, China
| | - Wei He
- Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), No. 1 Jiazi Road, Lunjiao, Shunde District, Foshan, 528308, Guangdong Province, China
| | - Weijie Zhang
- Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), No. 1 Jiazi Road, Lunjiao, Shunde District, Foshan, 528308, Guangdong Province, China
| | - Jing Ma
- Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), No. 1 Jiazi Road, Lunjiao, Shunde District, Foshan, 528308, Guangdong Province, China
| | - Weidong Wang
- Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), No. 1 Jiazi Road, Lunjiao, Shunde District, Foshan, 528308, Guangdong Province, China.
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24
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Mangum DS, Meyer JA, Mason CC, Shams S, Maese LD, Gardiner JD, Downie JM, Pei D, Cheng C, Gleason A, Luo M, Pui CH, Aplenc R, Hunger SP, Loh M, Greaves M, Trede N, Raetz E, Frazer JK, Mullighan CG, Engel ME, Miles RR, Rabin KR, Schiffman JD. Association of Combined Focal 22q11.22 Deletion and IKZF1 Alterations With Outcomes in Childhood Acute Lymphoblastic Leukemia. JAMA Oncol 2021; 7:1521-1528. [PMID: 34410295 DOI: 10.1001/jamaoncol.2021.2723] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Importance Alterations in the IKZF1 gene drive B-cell acute lymphoblastic leukemia (B-ALL) but are not routinely used to stratify patients by risk because of inconsistent associations with outcomes. We describe a novel deletion in 22q11.22 that was consistently associated with very poor outcomes in patients with B-ALL with IKZF1 alterations. Objective To determine whether focal deletions within the λ variable chain region in chromosome 22q11.22 were associated with patients with B-ALL with IKZF1 alterations with the highest risk of relapse and/or death. Design, Setting, and Participants This cohort study included 1310 primarily high-risk pediatric patients with B-ALL who were taken from 6 independent clinical cohorts, consisting of 3 multicenter cohorts (AALL0232 [2004-2011], P9906 [2000-2003], and patients with Down syndrome who were pooled from national and international studies) and 3 single-institution cohorts (University of Utah [Salt Lake City], Children's Hospital of Philadelphia [Philadelphia, Pennsylvania], and St. Jude Children's Hospital [Memphis, Tennessee]). Data analysis began in 2011 using patients from the older studies first, and data analysis concluded in 2021. Exposures Focal 22q11.22 deletions. Main Outcomes and Measures Event-free and overall survival was investigated. The hypothesis that 22q11.22 deletions stratified the prognostic effect of IKZF1 alterations was formulated while investigating nearby deletions in VPREB1 in 2 initial cohorts (n = 270). Four additional cohorts were then obtained to further study this association (n = 1040). Results This study of 1310 patients with B-ALL (717 male [56.1%] and 562 female patients [43.9%]) found that focal 22q11.22 deletions are frequent (518 of 1310 [39.5%]) in B-ALL and inconsistent with physiologic V(D)J recombination. A total of 299 of 1310 patients with B-ALL had IKZF1 alterations. Among patients with IKZF1 alterations, more than half shared concomitant focal 22q11.22 deletions (159 of 299 [53.0%]). Patients with combined IKZF1 alterations and 22q11.22 deletions had worse outcomes compared with patients with IKZF1 alterations and wild-type 22q11.22 alleles in every cohort examined (combined cohorts: 5-year event-free survival rates, 43.3% vs 68.5%; hazard ratio [HR], 2.18; 95% CI, 1.54-3.07; P < .001; 5-year overall survival rates, 66.9% vs 83.9%; HR, 2.05; 95% CI, 1.32-3.21; P = .001). While 22q11.22 deletions were not prognostic in patients with wild-type IKZF1 , concomitant 22q11.22 deletions in patients with IKZF1 alterations stratified outcomes across additional risk groups, including patients who met the IKZF1plus criteria, and maintained independent significance in multivariate analysis for event-free survival (HR, 2.05; 95% CI, 1.27-3.29; P = .003) and overall survival (HR, 1.83; 95% CI, 1.01-3.34; P = .05). Conclusions and Relevance This cohort study suggests that 22q11.22 deletions identify patients with B-ALL and IKZF1 alterations who have very poor outcomes and may offer a new genetic biomarker to further refine B-ALL risk stratification and treatment strategies.
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Affiliation(s)
- David Spencer Mangum
- Nemours/Alfred I. DuPont Hospital for Children, Division of Pediatric Hematology/Oncology, Wilmington, Delaware
| | - Julia A Meyer
- Division of Pediatric Hematology & Oncology, Department of Pediatrics, University of Utah, Salt Lake City.,Division of Pediatric Hematology and Oncology, University of California, San Francisco
| | - Clinton C Mason
- Division of Pediatric Hematology & Oncology, Department of Pediatrics, University of Utah, Salt Lake City
| | | | - Luke D Maese
- Division of Pediatric Hematology & Oncology, Department of Pediatrics, University of Utah, Salt Lake City
| | - Jamie D Gardiner
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City
| | | | - Deqing Pei
- Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Cheng Cheng
- Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Adam Gleason
- Department of Pathology & Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Minjie Luo
- Department of Pathology & Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Ching-Hon Pui
- Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Richard Aplenc
- Division of Oncology and the Center for Childhood Cancer Research, The Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia
| | - Stephen P Hunger
- Division of Oncology and the Center for Childhood Cancer Research, The Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia
| | - Mignon Loh
- Division of Pediatric Hematology and Oncology, University of California, San Francisco
| | - Mel Greaves
- Institute of Cancer Research, London, England
| | | | - Elizabeth Raetz
- Department of Pediatrics, NYU Langone Health, New York, New York
| | - J Kimble Frazer
- Jimmy Everest Section of Pediatric Hematology-Oncology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City
| | - Charles G Mullighan
- Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Michael E Engel
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Virginia, Charlottesville
| | - Rodney R Miles
- Department of Pathology, University of Utah Health Sciences Center, Salt Lake City
| | - Karen R Rabin
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Joshua D Schiffman
- Division of Pediatric Hematology & Oncology, Department of Pediatrics, University of Utah, Salt Lake City.,Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City.,PEEL Therapeutics, Inc, Salt Lake City, Utah
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Chhabra S, Warmflash A. BMP-treated human embryonic stem cells transcriptionally resemble amnion cells in the monkey embryo. Biol Open 2021; 10:271874. [PMID: 34435204 PMCID: PMC8502258 DOI: 10.1242/bio.058617] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 08/05/2021] [Indexed: 12/17/2022] Open
Abstract
Human embryonic stem cells (hESCs) possess an immense potential to generate clinically relevant cell types and unveil mechanisms underlying early human development. However, using hESCs for discovery or translation requires accurately identifying differentiated cell types through comparison with their in vivo counterparts. Here, we set out to determine the identity of much debated BMP-treated hESCs by comparing their transcriptome to recently published single cell transcriptomic data from early human embryos (
Xiang et al., 2020). Our analyses reveal several discrepancies in the published human embryo dataset, including misclassification of putative amnion, intermediate and inner cell mass cells. These misclassifications primarily resulted from similarities in pseudogene expression, highlighting the need to carefully consider gene lists when making comparisons between cell types. In the absence of a relevant human dataset, we utilized the recently published single cell transcriptome of the early post implantation monkey embryo to discern the identity of BMP-treated hESCs. Our results suggest that BMP-treated hESCs are transcriptionally more similar to amnion cells than trophectoderm cells in the monkey embryo. Together with prior studies, this result indicates that hESCs possess a unique ability to form mature trophectoderm subtypes via an amnion-like transcriptional state. This article has an associated First Person interview with the first author of the paper. Summary: We show that BMP-treated human embryonic stem cells (hESCs) are more likely to represent an amnion rather than a trophectoderm cell type.
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Affiliation(s)
- Sapna Chhabra
- Systems Synthetic and Physical Biology graduate program, Rice University, Houston, TX 77005, USA.,Department of Biosciences, Rice University, Houston, TX 77005, USA
| | - Aryeh Warmflash
- Department of Biosciences, Rice University, Houston, TX 77005, USA.,Department of Bioengineering, Rice University, Houston, TX 77005, USA
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26
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The fish pathogen Aliivibrio salmonicida LFI1238 can degrade and metabolize chitin despite major gene loss in the chitinolytic pathway. Appl Environ Microbiol 2021; 87:e0052921. [PMID: 34319813 DOI: 10.1128/aem.00529-21] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The fish pathogen Aliivibrio (Vibrio) salmonicida LFI1238 is thought to be incapable of utilizing chitin as a nutrient source since approximately half of the genes representing the chitinolytic pathway are disrupted by insertion sequences. In the present study, we combined a broad set of analytical methods to investigate this hypothesis. Cultivation studies revealed that Al. salmonicida grew efficiently on N-acetylglucosamine (GlcNAc) and chitobiose ((GlcNAc)2), the primary soluble products resulting from enzymatic chitin hydrolysis. The bacterium was also able to grow on chitin particles, albeit at a lower rate compared to the soluble substrates. The genome of the bacterium contains five disrupted chitinase genes (pseudogenes) and three intact genes encoding a glycoside hydrolase family 18 (GH18) chitinase and two auxiliary activity family 10 (AA10) lytic polysaccharide monooxygenases (LPMOs). Biochemical characterization showed that the chitinase and LPMOs were able to depolymerize both α- and β-chitin to (GlcNAc)2 and oxidized chitooligosaccharides, respectively. Notably, the chitinase displayed up to 50-fold lower activity compared to other well-studied chitinases. Deletion of the genes encoding the intact chitinolytic enzymes showed that the chitinase was important for growth on β-chitin, whereas the LPMO gene-deletion variants only showed minor growth defects on this substrate. Finally, proteomic analysis of Al. salmonicida LFI1238 growth on β-chitin showed expression of all three chitinolytic enzymes, and intriguingly also three of the disrupted chitinases. In conclusion, our results show that Al. salmonicida LFI1238 can utilize chitin as a nutrient source and that the GH18 chitinase and the two LPMOs are needed for this ability. IMPORTANCE The ability to utilize chitin as a source of nutrients is important for the survival and spread of marine microbial pathogens in the environment. One such pathogen is Aliivibrio (Vibrio) salmonicida, the causative agent of cold water vibriosis. Due to extensive gene decay, many key enzymes in the chitinolytic pathway have been disrupted, putatively rendering this bacterium incapable of chitin degradation and utilization. In the present study we demonstrate that Al. salmonicida can degrade and metabolize chitin, the most abundant biopolymer in the ocean. Our findings shed new light on the environmental adaption of this fish pathogen.
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27
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Srivastava SP, Goodwin JE, Tripathi P, Kanasaki K, Koya D. Interactions among Long Non-Coding RNAs and microRNAs Influence Disease Phenotype in Diabetes and Diabetic Kidney Disease. Int J Mol Sci 2021; 22:ijms22116027. [PMID: 34199672 PMCID: PMC8199750 DOI: 10.3390/ijms22116027] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/21/2021] [Accepted: 05/27/2021] [Indexed: 02/07/2023] Open
Abstract
Large-scale RNA sequencing and genome-wide profiling data revealed the identification of a heterogeneous group of noncoding RNAs, known as long noncoding RNAs (lncRNAs). These lncRNAs play central roles in health and disease processes in diabetes and cancer. The critical association between aberrant expression of lncRNAs in diabetes and diabetic kidney disease have been reported. LncRNAs regulate diverse targets and can function as sponges for regulatory microRNAs, which influence disease phenotype in the kidneys. Importantly, lncRNAs and microRNAs may regulate bidirectional or crosstalk mechanisms, which need to be further investigated. These studies offer the novel possibility that lncRNAs may be used as potential therapeutic targets for diabetes and diabetic kidney diseases. Here, we discuss the functions and mechanisms of actions of lncRNAs, and their crosstalk interactions with microRNAs, which provide insight and promise as therapeutic targets, emphasizing their role in the pathogenesis of diabetes and diabetic kidney disease.
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Affiliation(s)
- Swayam Prakash Srivastava
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06511, USA;
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06511, USA
- Correspondence: or (S.P.S.); (D.K.)
| | - Julie E. Goodwin
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06511, USA;
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Pratima Tripathi
- Department of Biochemistry, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow 226010, India;
| | - Keizo Kanasaki
- Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-0021, Japan;
| | - Daisuke Koya
- Department of Diabetology and Endocrinology, Kanazawa Medical University, Ishikawa 920-0293, Japan
- Correspondence: or (S.P.S.); (D.K.)
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28
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Host Genome-Wide Association Study of Infant Susceptibility to Shigella-Associated Diarrhea. Infect Immun 2021; 89:IAI.00012-21. [PMID: 33649051 PMCID: PMC8316060 DOI: 10.1128/iai.00012-21] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 02/22/2021] [Indexed: 12/15/2022] Open
Abstract
Shigella is a leading cause of moderate-to-severe diarrhea globally and the causative agent of shigellosis and bacillary dysentery. Associated with 80 to 165 million cases of diarrhea and >13% of diarrheal deaths, in many regions, Shigella exposure is ubiquitous while infection is heterogenous. To characterize host-genetic susceptibility to Shigella-associated diarrhea, we performed two independent genome-wide association studies (GWAS) including Bangladeshi infants from the PROVIDE and CBC birth cohorts in Dhaka, Bangladesh. Cases were infants with Shigella-associated diarrhea (n = 143) and controls were infants with no Shigella-associated diarrhea in the first 13 months of life (n = 446). Shigella-associated diarrhea was identified via quantitative PCR (qPCR) threshold cycle (CT ) distributions for the ipaH gene, carried by all four Shigella species and enteroinvasive Escherichia coli Host GWAS were performed under an additive genetic model. A joint analysis identified protective loci on chromosomes 11 (rs582240, within the KRT18P59 pseudogene; P = 6.40 × 10-8; odds ratio [OR], 0.43) and 8 (rs12550437, within the lincRNA RP11-115J16.1; P = 1.49 × 10-7; OR, 0.48). Conditional analyses identified two previously suggestive loci, a protective locus on chromosome 7 (rs10266841, within the 3' untranslated region [UTR] of CYTH3; P conditional = 1.48 × 10-7; OR, 0.44) and a risk-associated locus on chromosome 10 (rs2801847, an intronic variant within MPP7; P conditional = 8.37 × 10-8; OR, 5.51). These loci have all been indirectly linked to bacterial type 3 secretion system (T3SS) activity, its components, and bacterial effectors delivered into host cells. Host genetic factors that may affect bacterial T3SS activity and are associated with the host response to Shigella-associated diarrhea may provide insight into vaccine and drug development efforts for Shigella-associated diarrheal disease.
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29
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Vijayan M, Reddy PH. Non-Coding RNAs Based Molecular Links in Type 2 Diabetes, Ischemic Stroke, and Vascular Dementia. J Alzheimers Dis 2021; 75:353-383. [PMID: 32310177 DOI: 10.3233/jad-200070] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This article reviews recent advances in the study of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and their functions in type 2 diabetes mellitus (T2DM), ischemic stroke (IS), and vascular dementia (VaD). miRNAs and lncRNAs are gene regulation markers that both regulate translational aspects of a wide range of proteins and biological processes in healthy and disease states. Recent studies from our laboratory and others have revealed that miRNAs and lncRNAs expressed differently are potential therapeutic targets for neurological diseases, especially T2DM, IS, VaD, and Alzheimer's disease (AD). Currently, the effect of aging in T2DM, IS, and VaD and the cellular and molecular pathways are largely unknown. In this article, we highlight results from the works on the molecular connections between T2DM and IS, and IS and VaD. In each disease, we also summarize the pathophysiology and the differential expressions of miRNAs and lncRNAs. Based on current research findings, we hypothesize that 1) T2DM bi-directionally and age-dependently induces IS and VaD, and 2) these changes are precursors to the onset of dementia in elderly people. Research into these hypotheses is required to examine further whether research efforts on reducing T2DM, IS, and VaD may affect dementia and/or delay the AD disease process in the aged population.
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Affiliation(s)
- Murali Vijayan
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Department of Speech, Language and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA
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30
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Abstract
Long noncoding RNAs (lncRNAs) are involved in many regulatory mechanisms in practically every step of the RNA cycle, from transcription to RNA stability and translation. They are a highly heterogeneous class of molecules in terms of site of production, interaction networks, and functions. More and more databases are available on the web with the aim to make public information about lncRNA accessible to the scientific community. Here we review the most interesting resources with the purpose to organize a compendium of useful tools to interrogate before studying a lncRNA of interest.
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31
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Hu Y, Zhang X, Zai HY, Jiang W, Xiao L, Zhu Q. lncRNA DUXAP8 Facilitates Multiple Malignant Phenotypes and Resistance to PARP Inhibitor in HCC via Upregulating FOXM1. MOLECULAR THERAPY-ONCOLYTICS 2020; 19:308-322. [PMID: 33313387 PMCID: PMC7701012 DOI: 10.1016/j.omto.2020.10.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 10/17/2020] [Indexed: 02/08/2023]
Abstract
In this study, we examined the clinical significance and molecular mechanisms of a long non-coding RNA (lncRNA), double homeobox A pseudogene 8 (DUXAP8) in hepatocellular carcinoma (HCC). DUXAP8 expression was compared using quantitative real-time PCR in HCC versus adjacent tissues and in HCC cell lines versus normal hepatic epithelial cells. The correlations between DUXAP8 level and clinicopathological features were analyzed. Assays including MTT, colony-forming analysis, Transwell assay, western blot, xenograft formation, experimental metastasis, luciferase assay, RNA pull-down, and RNA immunoprecipitation were used to examine DUXAP8-induced malignant phenotypes, its regulation on forkhead box protein M1 (FOXM1), and the importance of FOXM1 in mediating DUXAP8 phenotypes. Our results showed that DUXAP8 was significantly upregulated in HCC tissues or cell lines associated with tumors of advanced grades, tumors that were positive for lymph node metastasis, and patients with poor overall survival. DUAXP8 was essential in maintaining multiple malignant phenotypes (including resistance to olaparib) both in vitro and in vivo. Mechanistically, DUXAP8 upregulated FOXM1 expression by sponging miR-485-5p and interacting with the RNA-binding protein Fused in Sarcoma (FUS). Functionally, FOXM1 essentially mediated the oncogenic phenotypes of DUXAP8. Collectively, DUXAP8 acts through two distinct mechanisms to upregulate FOXM1 and becomes a pleotropic oncogenic lncRNA in HCC.
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Affiliation(s)
- Yu Hu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, P.R. China
| | - Xian Zhang
- Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha 410008, Hunan Province, P.R. China
| | - Hong-Yan Zai
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, P.R. China
| | - Wei Jiang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, P.R. China
| | - Liang Xiao
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, P.R. China
| | - Qin Zhu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, P.R. China
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32
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De Martino M, Esposito F, Fusco A. The HMGA1-pseudogene7 shows oncogenic activity in vivo. Cell Cycle 2020; 19:2955-2959. [PMID: 33043837 DOI: 10.1080/15384101.2020.1829825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
We have recently reported that transgenic mice overexpressing the HMGA1-pseudogene7 develop hematological neoplasia marked by monoclonal B-cell populations, and diagnosed as Diffuse Large B-cell Lymphoma. These findings prove the HMGA1-pseudogene7 oncogenic role in vivo.
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Affiliation(s)
- Marco De Martino
- Istituto di Endocrinologia ed Oncologia Sperimentale - CNR C/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Degli Studi di Napoli "Federico II" , Naples, Italy
| | - Francesco Esposito
- Istituto di Endocrinologia ed Oncologia Sperimentale - CNR C/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Degli Studi di Napoli "Federico II" , Naples, Italy
| | - Alfredo Fusco
- Istituto di Endocrinologia ed Oncologia Sperimentale - CNR C/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Degli Studi di Napoli "Federico II" , Naples, Italy
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33
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Sun Q, Song YJ, Prasanth KV. One locus with two roles: microRNA-independent functions of microRNA-host-gene locus-encoded long noncoding RNAs. WILEY INTERDISCIPLINARY REVIEWS-RNA 2020; 12:e1625. [PMID: 32945142 PMCID: PMC7965793 DOI: 10.1002/wrna.1625] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/22/2020] [Accepted: 08/08/2020] [Indexed: 12/14/2022]
Abstract
Long noncoding RNAs (lncRNAs) are RNA transcripts longer than 200 nucleotides that do not code for proteins. LncRNAs play crucial regulatory roles in several biological processes via diverse mechanisms and their aberrant expression is associated with various diseases. LncRNA genes are further subcategorized based on their relative organization in the genome. MicroRNA (miRNA)-host-gene-derived lncRNAs (lnc-MIRHGs) refer to lncRNAs whose genes also harbor miRNAs. There exists crosstalk between the processing of lnc-MIRHGs and the biogenesis of the encoded miRNAs. Although the functions of the encoded miRNAs are usually well understood, whether those lnc-MIRHGs play independent functions are not fully elucidated. Here, we review our current understanding of lnc-MIRHGs, including their biogenesis, function, and mechanism of action, with a focus on discussing the miRNA-independent functions of lnc-MIRHGs, including their involvement in cancer. Our current understanding of lnc-MIRHGs strongly indicates that this class of lncRNAs could play important roles in basic cellular events as well as in diseases. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs.
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Affiliation(s)
- Qinyu Sun
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - You Jin Song
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - Kannanganattu V Prasanth
- Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.,Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
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Lin JZ, Lin N, Zhao WJ. Identification and validation of a six-lncRNA prognostic signature with its ceRNA networks and candidate drugs in lower-grade gliomas. Genomics 2020; 112:2990-3002. [PMID: 32447005 DOI: 10.1016/j.ygeno.2020.05.016] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/08/2020] [Accepted: 05/18/2020] [Indexed: 02/05/2023]
Abstract
Gliomas account for 75% of the primary malignant brain tumors and a majority of lower-grade gliomas (LGG) inevitably develop into glioblastoma. The dysregulation of lncRNAs play a crucial role in LGG. In the present study, we first screened out six differentially expressed lncRNAs (AC021739.2, AL031722.1, AL354740.1, FGD5-AS1, LINC00844, and NEAT1) based on TCGA and GTEx RNA-seq databases. LncRNA prognostic signature was then established by Kaplan-Meier and multivariate Cox proportional hazards regression, with its predictive value validated by time-dependent receiver operating characteristic (ROC) curves. After lncRNA-miRNA-mRNA regulatory networks were established by Cytoscape 3.7.2, Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed, with results enriched in various malignancy-related functions and pathways. Finally, six putative drugs (irinotecan, camptothecin, mitoxantrone, azacitidine, mestranol, and enilconazole) were predicted by Connectivity Map. In conclusion, we identified a 6-lncRNA prognostic signature with its ceRNA networks, and six candidate drugs against LGG.
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Affiliation(s)
- Jia-Zhe Lin
- Neurosurgical Department, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Nuan Lin
- Obstetrics & Gynecology Department, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Wei-Jiang Zhao
- Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China.
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Cao L, Wang Y, Bi C, Ye Q, Yin T, Ye N. PreLnc: An Accurate Tool for Predicting lncRNAs Based on Multiple Features. Genes (Basel) 2020; 11:E981. [PMID: 32842486 PMCID: PMC7563287 DOI: 10.3390/genes11090981] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/19/2020] [Accepted: 08/21/2020] [Indexed: 01/13/2023] Open
Abstract
Accumulating evidence indicates that long non-coding RNAs (lncRNAs) have certain similarities with messenger RNAs (mRNAs) and are associated with numerous important biological processes, thereby demanding methods to distinguish them. Based on machine learning algorithms, a variety of methods are developed to identify lncRNAs, providing significant basic data support for subsequent studies. However, many tools lack certain scalability, versatility and balance, and some tools rely on genome sequence and annotation. In this paper, we propose a convenient and accurate tool "PreLnc", which uses high-confidence lncRNA and mRNA transcripts to build prediction models through feature selection and classifiers. The false discovery rate (FDR) adjusted P-value and Z-value were used for analyzing the tri-nucleotide composition of transcripts of different species. Conclusions can be drawn from the experiment that there were significant differences in RNA transcripts among plants, which may be related to evolutionary conservation and the fact that plants are under evolutionary pressure for a longer time than animals. Combining with the Pearson correlation coefficient, we use the incremental feature selection (IFS) method and the comparison of multiple classifiers to build the model. Finally, the balanced random forest was used to construct the classifier, and PreLnc obtained 91.09% accuracy for 349,186 transcripts of animals and plants. In addition, by comparing standard performance measurements, PreLnc performed better than other prediction tools.
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Affiliation(s)
- Lei Cao
- College of Information Science and Technology, Nanjing Forestry University, Nanjing 210037, China; (L.C.); (Y.W.); (Q.Y.)
| | - Yupeng Wang
- College of Information Science and Technology, Nanjing Forestry University, Nanjing 210037, China; (L.C.); (Y.W.); (Q.Y.)
| | - Changwei Bi
- School of Biological Science and Medical Engineering, Southeast University, Nanjing 210037, China;
| | - Qiaolin Ye
- College of Information Science and Technology, Nanjing Forestry University, Nanjing 210037, China; (L.C.); (Y.W.); (Q.Y.)
| | - Tongming Yin
- The Key Lab of Cultivar Innovation and Germplasm Improvement of Salicaceae, College of Forestry, Nanjing Forestry University, Nanjing 210037, China;
| | - Ning Ye
- College of Information Science and Technology, Nanjing Forestry University, Nanjing 210037, China; (L.C.); (Y.W.); (Q.Y.)
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Tian H, Guo F, Zhang Z, Ding H, Meng J, Li X, Peng Z, Wan S. Discovery, identification, and functional characterization of long noncoding RNAs in Arachis hypogaea L. BMC PLANT BIOLOGY 2020; 20:308. [PMID: 32615935 PMCID: PMC7330965 DOI: 10.1186/s12870-020-02510-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 06/22/2020] [Indexed: 05/10/2023]
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs), which are typically > 200 nt in length, are involved in numerous biological processes. Studies on lncRNAs in the cultivated peanut (Arachis hypogaea L.) largely remain unknown. RESULTS A genome-wide scan of the peanut (Arachis hypogaea L.) transcriptome identified 1442 lncRNAs, which were encoded by loci distributed over every chromosome. Long intergenic noncoding RNAs accounted for 85.58% of these lncRNAs. Additionally, 189 lncRNAs were differentially abundant in the root, leaf, or seed. Generally, lncRNAs showed lower expression levels, tighter tissue-specific expression, and less splicing than mRNAs. Approximately 44.17% of the lncRNAs with an exon/intron structure were alternatively spliced; this rate was slightly lower than the splicing rate of mRNA. Transcription at the start site event was the alternative splicing (AS) event with the highest frequency (28.05%) in peanut lncRNAs, whereas the occurrence rate (30.19%) of intron retention event was the highest in mRNAs. AS changed the target gene profiles of lncRNAs and increased the diversity and flexibility of lncRNAs, which may be important for lncRNAs to execute their functions. Additionally, a substantial number of the peanut AS isoforms generated from protein-encoding genes appeared to be noncoding because they were truncated transcripts; such isoforms can be legitimately regarded as a class of lncRNAs. The predicted target genes of the lncRNAs were involved in a wide range of biological processes. Furthermore, expression pattern of several selected lncRNAs and their target genes were examined under salt stress, results showed that all of them could respond to salt stress in different manners. CONCLUSIONS This study provided a resource of candidate lncRNAs and expression patterns across tissues, and whether these lncRNAs are functional will be further investigated in our subsequent experiments.
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Affiliation(s)
- Haiying Tian
- College of Life Science, Shandong University, Jinan, 250014 China
| | - Feng Guo
- Bio-Tech Research Center, Shandong Academy of Agricultural Science/Shandong Provincial Key Laboratory of Genetic Improvement, Ecology and Physiology of Crops, Jinan, 250014 China
| | - Zhimeng Zhang
- Peanut Research Institute of Shandong, Qingdao, 266100 China
| | - Hong Ding
- Peanut Research Institute of Shandong, Qingdao, 266100 China
| | - Jingjing Meng
- Bio-Tech Research Center, Shandong Academy of Agricultural Science/Shandong Provincial Key Laboratory of Genetic Improvement, Ecology and Physiology of Crops, Jinan, 250014 China
| | - Xinguo Li
- College of Life Science, Shandong University, Jinan, 250014 China
- Bio-Tech Research Center, Shandong Academy of Agricultural Science/Shandong Provincial Key Laboratory of Genetic Improvement, Ecology and Physiology of Crops, Jinan, 250014 China
| | - Zhenying Peng
- College of Life Science, Shandong University, Jinan, 250014 China
- Bio-Tech Research Center, Shandong Academy of Agricultural Science/Shandong Provincial Key Laboratory of Genetic Improvement, Ecology and Physiology of Crops, Jinan, 250014 China
| | - Shubo Wan
- College of Life Science, Shandong University, Jinan, 250014 China
- Shandong Academy of Agricultural Science, Jinan, 250014 China
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An Overview of Non-coding RNAs and Cardiovascular System. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1229:3-45. [PMID: 32285403 DOI: 10.1007/978-981-15-1671-9_1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cardiovascular disease management and timely diagnosis remain a major dilemma. Delineating molecular mechanisms of cardiovascular diseases is opening horizon in the field of molecular medicines and in the development of early diagnostic markers. Non-coding RNAs are the highly functional and vibrant nucleic acids and are known to be involved in the regulation of endothelial cells, vascular and smooth muscles cells, cardiac metabolism, ischemia, inflammation and many processes in cardiovascular system. This chapter is comprehensively focusing on the overview of the non-coding RNAs including their discovery, generation, classification and functional regulation. In addition, overview regarding different non-coding RNAs as long non-coding, siRNAs and miRNAs involvement in the cardiovascular diseases is also addressed. Detailed functional analysis of this vast group of highly regulatory molecules will be promising for shaping future drug discoveries.
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Fumero MV, Villani A, Susca A, Haidukowski M, Cimmarusti MT, Toomajian C, Leslie JF, Chulze SN, Moretti A. Fumonisin and Beauvericin Chemotypes and Genotypes of the Sister Species Fusarium subglutinans and Fusarium temperatum. Appl Environ Microbiol 2020; 86:e00133-20. [PMID: 32358011 PMCID: PMC7301838 DOI: 10.1128/aem.00133-20] [Citation(s) in RCA: 11] [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: 01/17/2020] [Accepted: 04/28/2020] [Indexed: 12/19/2022] Open
Abstract
Fusarium subglutinans and Fusarium temperatum are common maize pathogens that produce mycotoxins and cause plant disease. The ability of these species to produce beauvericin and fumonisin mycotoxins is not settled, as reports of toxin production are not concordant. Our objective was to clarify this situation by determining both the chemotypes and genotypes for strains from both species. We analyzed 25 strains from Argentina, 13 F. subglutinans and 12 F. temperatum strains, for toxin production by ultraperformance liquid chromatography mass spectrometry (UPLC-MS). We used new genome sequences from two strains of F. subglutinans and one strain of F. temperatum, plus genomes of other Fusarium species, to determine the presence of functional gene clusters for the synthesis of these toxins. None of the strains examined from either species produced fumonisins. These strains also lack Fum biosynthetic genes but retain homologs of some genes that flank the Fum cluster in Fusarium verticillioides None of the F. subglutinans strains we examined produced beauvericin although 9 of 12 F. temperatum strains did. A complete beauvericin (Bea) gene cluster was present in all three new genome sequences. The Bea1 gene was presumably functional in F. temperatum but was not functional in F. subglutinans due to a large insertion and multiple mutations that resulted in premature stop codons. The accumulation of only a few mutations expected to disrupt Bea1 suggests that the process of its inactivation is relatively recent. Thus, none of the strains of F. subglutinans or F. temperatum we examined produce fumonisins, and the strains of F. subglutinans examined also cannot produce beauvericin. Variation in the ability of strains of F. temperatum to produce beauvericin requires further study and could reflect the recent shared ancestry of these two species.IMPORTANCEFusarium subglutinans and F. temperatum are sister species and maize pathogens commonly isolated worldwide that can produce several mycotoxins and cause seedling disease, stalk rot, and ear rot. The ability of these species to produce beauvericin and fumonisin mycotoxins is not settled, as reports of toxin production are not concordant at the species level. Our results are consistent with previous reports that strains of F. subglutinans produce neither fumonisins nor beauvericin. The status of toxin production by F. temperatum needs further work. Our strains of F. temperatum did not produce fumonisins, while some strains produced beauvericin and others did not. These results enable more accurate risk assessments of potential mycotoxin contamination if strains of these species are present. The nature of the genetic inactivation of BEA1 is consistent with its relatively recent occurrence and the close phylogenetic relationship of the two sister species.
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Affiliation(s)
- M Veronica Fumero
- Research Institute on Mycology and Mycotoxicology, National Research Council of Argentina, National University of Rio Cuarto, Rio Cuarto, Cordoba, Argentina
| | | | - Antonia Susca
- Institute of Sciences of Food Production, CNR, Bari, Italy
| | | | | | | | - John F Leslie
- Department of Plant Pathology, Kansas State University, Manhattan, Kansas, USA
| | - Sofia N Chulze
- Research Institute on Mycology and Mycotoxicology, National Research Council of Argentina, National University of Rio Cuarto, Rio Cuarto, Cordoba, Argentina
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RNA-seq reveals downregulated osteochondral genes potentially related to tibia bacterial chondronecrosis with osteomyelitis in broilers. BMC Genet 2020; 21:58. [PMID: 32493207 PMCID: PMC7271470 DOI: 10.1186/s12863-020-00862-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 05/18/2020] [Indexed: 12/14/2022] Open
Abstract
Background Bacterial chondronecrosis with osteomyelitis (BCO) develops in the growth plate (GP) of the proximal femur and tibia and is initiated by damage to the less mineralized chondrocytes followed by colonization of opportunistic bacteria. This condition affects approximately 1% of all birds housed, being considered one of the major causes of lameness in fast growing broilers. Although several studies have been previously performed aiming to understand its pathogenesis, the molecular mechanisms involved with BCO remains to be elucidated. Therefore, this study aimed to generate a profile of global differential gene expression involved with BCO in the tibia of commercial broilers, through RNA sequencing analysis to identity genes and molecular pathways involved with BCO in chickens. Results Our data showed 192 differentially expressed (DE) genes: 63 upregulated and 129 downregulated in the GP of the tibia proximal epiphysis of BCO-affected broilers. Using all DE genes, six Biological Processes (BP) were associated with bone development (connective tissue development, cartilage development, skeletal system development, organ morphogenesis, system development and skeletal system morphogenesis). The analyses of the upregulated genes did not indicate any significant BP (FDR < 0.05). However, with the downregulated genes, the same BP were identified when using all DE genes in the analysis, with a total of 26 coding genes explaining BCO in the tibia: ACAN, ALDH1A2, CDH7, CHAD, CHADL, COL11A1, COMP, CSGALNACT1, CYR61, FRZB, GAL3ST1, HAPLN1, IHH, KIF26B, LECT1, LPPR1, PDE6B, RBP4A, SERINC5, SFRP1, SOX8, SOX9, TENM2, THBS1, UCHL1 and WFIKKN2. In addition, seven transcription factors were also associated to BCO: NFATC2, MAFB, HIF1A-ARNT, EWSR1-FLI1, NFIC, TCF3 and NF-KAPPAB. Conclusions Our data show that osteochondral downregulated genes are potential molecular causes of BCO in broilers, and the bacterial process seems to be, in fact, a secondary condition. Sixteen genes responsible for bone and cartilage formation were downregulated in BCO-affected broilers being strong candidate genes to trigger this disorder.
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Kalenik BM, Góra-Sochacka A, Stachyra A, Olszewska-Tomczyk M, Fogtman A, Sawicka R, Śmietanka K, Sirko A. Response to a DNA vaccine against the H5N1 virus depending on the chicken line and number of doses. Virol J 2020; 17:66. [PMID: 32381003 PMCID: PMC7206725 DOI: 10.1186/s12985-020-01335-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/23/2020] [Indexed: 01/16/2023] Open
Abstract
Background Avian influenza virus infections cause significant economic losses on poultry farms and pose the threat of a possible pandemic outbreak. Routine vaccination of poultry against avian influenza is not recommended in Europe, however it has been ordered in some other countries, and more countries are considering use of the avian influenza vaccine as a component of their control strategy. Although a variety of such vaccines have been tested, most research has concentrated on specific antibodies and challenge experiments. Methods We monitored the transcriptomic response to a DNA vaccine encoding hemagglutinin from the highly pathogenic H5N1 avian influenza virus in the spleens of broiler and layer chickens. Moreover, in layer chickens the response to one and two doses of the vaccine was compared. Results All groups of birds immunized with two doses of the vaccine responded at the humoral level by producing specific anti-hemagglutinin antibodies. A response to the vaccine was also detected in the spleen transcriptomes. Differential expression of many genes encoding noncoding RNA and proteins functionally connected to the neuroendocrine-immune system was observed in different immunized groups. Conclusion Broiler chickens showed a higher number and wider range of fold-changes in the transcriptional response than laying hens.
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Affiliation(s)
- Barbara Małgorzata Kalenik
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, 02-106, Warsaw, Poland
| | - Anna Góra-Sochacka
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, 02-106, Warsaw, Poland
| | - Anna Stachyra
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, 02-106, Warsaw, Poland
| | - Monika Olszewska-Tomczyk
- Department of Poultry Diseases, National Veterinary Research Institute, Al. Partyzantow 57, 24-100, Puławy, Poland
| | - Anna Fogtman
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, 02-106, Warsaw, Poland
| | - Róża Sawicka
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, 02-106, Warsaw, Poland
| | - Krzysztof Śmietanka
- Department of Poultry Diseases, National Veterinary Research Institute, Al. Partyzantow 57, 24-100, Puławy, Poland
| | - Agnieszka Sirko
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, 02-106, Warsaw, Poland.
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Wells AC, Pobezinskaya EL, Pobezinsky LA. Non-coding RNAs in CD8 T cell biology. Mol Immunol 2020; 120:67-73. [PMID: 32085976 PMCID: PMC7093237 DOI: 10.1016/j.molimm.2020.01.023] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 01/17/2020] [Accepted: 01/29/2020] [Indexed: 12/12/2022]
Abstract
CD8 T cells are among the most vigorous soldiers of the immune system that fight viral infections and cancer. CD8 T cell development, maintenance, activation and differentiation are under the tight control of multiple transcriptional and post-transcriptional networks. Over the last two decades it has become clear that non-coding RNAs (ncRNAs), which consist of microRNAs (miRNAs) and long ncRNAs (lncRNAs), have emerged as global biological regulators. While our understanding of the function of specific miRNAs has increased since the discovery of RNA interference, it is still very limited, and the field of lncRNAs is just starting to blossom. Here we will summarize our knowledge on the role of ncRNAs in CD8 T cell biology, including differentiation into memory and exhausted cells.
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Affiliation(s)
- Alexandria C Wells
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, United States.
| | - Elena L Pobezinskaya
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, 01003, United States.
| | - Leonid A Pobezinsky
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, 01003, United States.
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DeVera C, Tosini G. Circadian analysis of the mouse retinal pigment epithelium transcriptome. Exp Eye Res 2020; 193:107988. [PMID: 32105725 DOI: 10.1016/j.exer.2020.107988] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 02/21/2020] [Accepted: 02/21/2020] [Indexed: 01/01/2023]
Abstract
The presence of a phagocytic peak of photoreceptor outer segments by the retinal pigment epithelium (RPE) one or 2 h after the onset of light has been reported for several diurnal and nocturnal species. This peak in phagocytic activity also persists under constant lighting conditions (i.e., constant light or dark) thus demonstrating that the timing of this peak is driven by a circadian clock. The aim of this study was to investigate the change in RPE whole transcriptome at two different circadian times (CT; 1 h before (CT23) and 1 h after (CT1) subjective light onset). C57BL/6J male mice were maintained in constant dark conditions for three days and euthanized under red light (<1 lux) at CT23 and CT1. RPE was isolated from whole eyes for RNA library preparation and sequencing on an Illumina HiSeq4000 platform. 14,083 mouse RPE transcripts were detected in common between CT23 and CT1. 12,005 were protein coding transcripts and 2078 were non-protein coding transcripts. 2421 protein coding transcripts were significantly upregulated whereas only 3 transcripts were significantly downregulated and 12 non-protein coding transcripts were significantly upregulated and 31 non-protein coding transcripts were significantly downregulated at CT1 when compared to CT23 (p < 0.05, fold change ≥ ±2.0). Of the protein coding transcripts, most of them were characterized as: enzymes, kinases, and transcriptional regulators with a large majority of activity in the cytoplasm, nucleus, and plasma membrane. Non-protein coding transcripts included biotypes such as long-non coding RNAs and pseudogenes. Gene ontology analysis and ingenuity pathway analysis revealed that differentially expressed transcripts were associated with integrin signaling, oxidative phosphorylation, protein phosphorylation, and actin cytoskeleton remodeling suggesting that these previously identified phagocytic pathways are under circadian control. Our analysis identified new pathways (e.g., increased mitochondrial respiration via increased oxidative phosphorylation) that may be involved in the circadian control of phagocytic activity. In addition, our dataset suggests a possible regulatory role for the identified non-protein coding transcripts in mediating the complex function of RPE phagocytosis. Finally, our results also indicate, as seen in other tissues, about 20% of the whole RPE transcriptome may be under circadian clock regulation.
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Affiliation(s)
- Christopher DeVera
- Department of Pharmacology and Toxicology, Atlanta, GA, USA, 30310; Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA, 30310
| | - Gianluca Tosini
- Department of Pharmacology and Toxicology, Atlanta, GA, USA, 30310; Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA, 30310.
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Sato K, Glaser S, Francis H, Alpini G. Concise Review: Functional Roles and Therapeutic Potentials of Long Non-coding RNAs in Cholangiopathies. Front Med (Lausanne) 2020; 7:48. [PMID: 32154257 PMCID: PMC7045865 DOI: 10.3389/fmed.2020.00048] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 01/31/2020] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are RNAs with lengths exceeding 200 nucleotides that are not translated into proteins. It is well-known that small non-coding RNAs, such as microRNAs (miRNAs), regulate gene expression and play an important role in cholangiopathies. Recent studies have demonstrated that lncRNAs may also play a key role in the pathophysiology of cholangiopathies. Patients with cholangiopathies often develop cholangiocarcinoma (CCA), which is cholangiocyte-derived cancer, in the later stage. Cholangiocytes are a primary target of therapies for cholangiopathies and CCA development. Previous studies have demonstrated that expression levels of lncRNAs are altered in the liver of cholangiopathies or CCA tissues. Some lncRNAs regulate gene expression by inhibiting functions of miRNAs leading to diseased liver conditions or CCA progression, suggesting that lncRNAs could be a novel therapeutic target for those disorders. This review summarizes current understandings of functional roles of lncRNAs in cholangiopathies and seek their potentials for novel therapies.
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Affiliation(s)
- Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University, College of Medicine, Bryan, TX, United States
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States
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Budak H, Kaya SB, Cagirici HB. Long Non-coding RNA in Plants in the Era of Reference Sequences. FRONTIERS IN PLANT SCIENCE 2020; 11:276. [PMID: 32226437 PMCID: PMC7080850 DOI: 10.3389/fpls.2020.00276] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 02/21/2020] [Indexed: 05/04/2023]
Abstract
The discovery of non-coding RNAs (ncRNAs), and the subsequent elucidation of their functional roles, was largely delayed due to the misidentification of non-protein-coding parts of DNA as "junk DNA," which forced ncRNAs into the shadows of their protein-coding counterparts. However, over the past decade, insight into the important regulatory roles of ncRNAs has led to rapid progress in their identification and characterization. Of the different types of ncRNAs, long non-coding RNAs (lncRNAs), has attracted considerable attention due to their mRNA-like structures and gene regulatory functions in plant stress responses. While RNA sequencing has been commonly used for mining lncRNAs, a lack of widespread conservation at the sequence level in addition to relatively low and highly tissue-specific expression patterns challenges high-throughput in silico identification approaches. The complex folding characteristics of lncRNA molecules also complicate target predictions, as the knowledge about the interaction interfaces between lncRNAs and potential targets is insufficient. Progress in characterizing lncRNAs and their targets from different species may hold the key to efficient identification of this class of ncRNAs from transcriptomic and potentially genomic resources. In wheat and barley, two of the most important crops, the knowledge about lncRNAs is very limited. However, recently published high-quality genomes of these crops are considered as promising resources for the identification of not only lncRNAs, but any class of molecules. Considering the increasing demand for food, these resources should be used efficiently to discover molecular mechanisms lying behind development and a/biotic stress responses. As our understanding of lncRNAs expands, interactions among ncRNA classes, as well as interactions with the coding sequences, will likely define novel functional networks that may be modulated for crop improvement.
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Affiliation(s)
- Hikmet Budak
- Montana BioAgriculture, Inc., Bozeman, MT, United States
- *Correspondence: Hikmet Budak,
| | - Sezgi Biyiklioglu Kaya
- Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Sabancı University, Istanbul, Turkey
| | - Halise Busra Cagirici
- Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Sabancı University, Istanbul, Turkey
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Johnson TS, Li S, Franz E, Huang Z, Dan Li S, Campbell MJ, Huang K, Zhang Y. PseudoFuN: Deriving functional potentials of pseudogenes from integrative relationships with genes and microRNAs across 32 cancers. Gigascience 2019; 8:5480571. [PMID: 31029062 PMCID: PMC6486473 DOI: 10.1093/gigascience/giz046] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 12/13/2018] [Accepted: 03/29/2019] [Indexed: 12/14/2022] Open
Abstract
Background Long thought “relics” of evolution, not until recently have pseudogenes been of medical interest regarding regulation in cancer. Often, these regulatory roles are a direct by-product of their close sequence homology to protein-coding genes. Novel pseudogene-gene (PGG) functional associations can be identified through the integration of biomedical data, such as sequence homology, functional pathways, gene expression, pseudogene expression, and microRNA expression. However, not all of the information has been integrated, and almost all previous pseudogene studies relied on 1:1 pseudogene–parent gene relationships without leveraging other homologous genes/pseudogenes. Results We produce PGG families that expand beyond the current 1:1 paradigm. First, we construct expansive PGG databases by (i) CUDAlign graphics processing unit (GPU) accelerated local alignment of all pseudogenes to gene families (totaling 1.6 billion individual local alignments and >40,000 GPU hours) and (ii) BLAST-based assignment of pseudogenes to gene families. Second, we create an open-source web application (PseudoFuN [Pseudogene Functional Networks]) to search for integrative functional relationships of sequence homology, microRNA expression, gene expression, pseudogene expression, and gene ontology. We produce four “flavors” of CUDAlign-based databases (>462,000,000 PGG pairwise alignments and 133,770 PGG families) that can be queried and downloaded using PseudoFuN. These databases are consistent with previous 1:1 PGG annotation and also are much more powerful including millions of de novo PGG associations. For example, we find multiple known (e.g., miR-20a-PTEN-PTENP1) and novel (e.g., miR-375-SOX15-PPP4R1L) microRNA-gene-pseudogene associations in prostate cancer. PseudoFuN provides a “one stop shop” for identifying and visualizing thousands of potential regulatory relationships related to pseudogenes in The Cancer Genome Atlas cancers. Conclusions Thousands of new PGG associations can be explored in the context of microRNA-gene-pseudogene co-expression and differential expression with a simple-to-use online tool by bioinformaticians and oncologists alike.
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Affiliation(s)
- Travis S Johnson
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, 1800 Cannon Drive, Columbus, OH 43210, USA.,Department of Medicine, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN 46202, USA
| | - Sihong Li
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, 1800 Cannon Drive, Columbus, OH 43210, USA
| | - Eric Franz
- Ohio Supercomputer Center, 1224 Kinnear Road, Columbus, OH 43212, USA
| | - Zhi Huang
- School of Electrical and Computer Engineering, Purdue University, 465 Northwestern Avenue, West Lafayette, IN 47907, USA.,Department of Medicine, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN 46202, USA
| | - Shuyu Dan Li
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Moray J Campbell
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, 500 West 12 th Avenue, Columbus, OH 43210, USA
| | - Kun Huang
- Department of Medicine, Indiana University School of Medicine, 545 Barnhill Drive, Indianapolis, IN 46202, USA.,Regenstrief Institute, Indiana University, 1101 West 10 th Street, Indianapolis, IN 46262, USA
| | - Yan Zhang
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, 1800 Cannon Drive, Columbus, OH 43210, USA.,The Ohio State University Comprehensive Cancer Center (OSUCCC - James), 460 West 10 th Avenue, Columbus, OH 43210, USA
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Barrow MA, Martin ME, Coffey A, Andrews PL, Jones GS, Reaves DK, Parker JS, Troester MA, Fleming JM. A functional role for the cancer disparity-linked genes, CRYβB2 and CRYβB2P1, in the promotion of breast cancer. Breast Cancer Res 2019; 21:105. [PMID: 31511085 PMCID: PMC6739962 DOI: 10.1186/s13058-019-1191-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 08/28/2019] [Indexed: 12/31/2022] Open
Abstract
Background In the USA, the breast cancer mortality rate is 41% higher for African-American women than non-Hispanic White women. While numerous gene expression studies have classified biological features that vary by race and may contribute to poorer outcomes, few studies have experimentally tested these associations. CRYβB2 gene expression has drawn particular interest because of its association with overall survival and African-American ethnicity in multiple cancers. Several reports indicate that overexpression of the CRYβB2 pseudogene, CRYβB2P1, and not CRYβB2 is linked with race and poor outcome. It remains unclear whether either or both genes are linked to breast cancer outcomes. This study investigates CRYβB2 and CRYβB2P1 expression in human breast cancers and breast cancer cell line models, with the goal of elucidating the mechanistic contribution of CRYβB2 and CRYβB2P1 to racial disparities. Methods Custom scripts for CRYβB2 or CRYβB2P1 were generated and used to identify reads that uniquely aligned to either gene. Gene expression according to race and tumor subtype were assessed using all available TCGA breast cancer RNA sequencing alignment samples (n = 1221). In addition, triple-negative breast cancer models engineered to have each gene overexpressed or knocked out were developed and evaluated by in vitro, biochemical, and in vivo assays to identify biological functions. Results We provide evidence that CRYβB2P1 is expressed at higher levels in breast tumors compared to CRYβB2, but only CRYβB2P1 is significantly increased in African-American tumors relative to White American tumors. We show that independent of CRYβB2, CRYβB2P1 enhances tumorigenesis in vivo via promoting cell proliferation. Our data also reveal that CRYβB2P1 may function as a non-coding RNA to regulate CRYβB2 expression. A key observation is that the combined overexpression of both genes was found to suppress cell growth. CRYβB2 overexpression in triple-negative breast cancers increases invasive cellular behaviors, tumor growth, IL6 production, immune cell chemoattraction, and the expression of metastasis-associated genes. These data underscore that both CRYβB2 and CRYβB2P1 promote tumor growth, but their mechanisms for tumor promotion are likely distinct. Conclusions Our findings provide novel data emphasizing the need to distinguish and study the biological effects of both CRYβB2 and CRYβB2P1 as both genes independently promote tumor progression. Our data demonstrate novel molecular mechanisms of two understudied, disparity-linked molecules. Electronic supplementary material The online version of this article (10.1186/s13058-019-1191-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Maya A Barrow
- Department of Biological and Biomedical Sciences, North Carolina Central University, 1801 Fayetteville Street, Mary Townes Science Complex, Durham, NC, 27707, USA
| | - Megan E Martin
- Department of Biological and Biomedical Sciences, North Carolina Central University, 1801 Fayetteville Street, Mary Townes Science Complex, Durham, NC, 27707, USA
| | - Alisha Coffey
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Portia L Andrews
- Department of Biological and Biomedical Sciences, North Carolina Central University, 1801 Fayetteville Street, Mary Townes Science Complex, Durham, NC, 27707, USA
| | - Gieira S Jones
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Denise K Reaves
- Department of Biological and Biomedical Sciences, North Carolina Central University, 1801 Fayetteville Street, Mary Townes Science Complex, Durham, NC, 27707, USA
| | - Joel S Parker
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Melissa A Troester
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jodie M Fleming
- Department of Biological and Biomedical Sciences, North Carolina Central University, 1801 Fayetteville Street, Mary Townes Science Complex, Durham, NC, 27707, USA. .,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Talyan S, Andrade-Navarro MA, Muro EM. Identification of transcribed protein coding sequence remnants within lincRNAs. Nucleic Acids Res 2019; 46:8720-8729. [PMID: 29986053 PMCID: PMC6158594 DOI: 10.1093/nar/gky608] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 06/26/2018] [Indexed: 12/21/2022] Open
Abstract
Long intergenic non-coding RNAs (lincRNAs) are non-coding transcripts >200 nucleotides long that do not overlap protein-coding sequences. Importantly, such elements are known to be tissue-specifically expressed and to play a widespread role in gene regulation across thousands of genomic loci. However, very little is known of the mechanisms for the evolutionary biogenesis of these RNA elements, especially given their poor conservation across species. It has been proposed that lincRNAs might arise from pseudogenes. To test this systematically, we developed a novel method that searches for remnants of protein-coding sequences within lincRNA transcripts; the hypothesis is that we can trace back their biogenesis from protein-coding genes or posterior transposon/retrotransposon insertions. Applying this method, we found 203 human lincRNA genes with regions significantly similar to protein-coding sequences. Our method provides a visualization tool to trace the evolutionary biogenesis of lincRNAs with respect to protein-coding genes by sequence divergence. Subsequently, we show the expression correlation between lincRNAs and their identified parental protein-coding genes using public RNA-seq repositories, hinting at novel gene regulatory relationships. In summary, we developed a novel computational methodology to study non-coding gene sequences, which can be applied to identify the evolutionary biogenesis and function of lincRNAs.
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Affiliation(s)
- Sweta Talyan
- Faculty of Biology, Johannes Gutenberg University of Mainz, 55128 Mainz, Germany.,Institute of Molecular Biology, 55128 Mainz, Germany
| | - Miguel A Andrade-Navarro
- Faculty of Biology, Johannes Gutenberg University of Mainz, 55128 Mainz, Germany.,Institute of Molecular Biology, 55128 Mainz, Germany
| | - Enrique M Muro
- Faculty of Biology, Johannes Gutenberg University of Mainz, 55128 Mainz, Germany.,Institute of Molecular Biology, 55128 Mainz, Germany
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Predictive value of circulating coagulation related microRNAs expressions for major adverse cardiac and cerebral event risk in patients undergoing continuous ambulatory peritoneal dialysis: a cohort study. J Nephrol 2019; 33:157-165. [PMID: 31359371 PMCID: PMC7007420 DOI: 10.1007/s40620-019-00626-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 06/20/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND We aimed to investigate the correlation of coagulation related microRNAs (miRNAs) expressions with major adverse cardiac and cerebral event (MACCE) risk in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). METHODS 198 end-stage renal disease (ESRD) patients underwent CAPD were consecutively recruited in this study. Clinical characteristics as well as physiological and biochemical indexes were recorded. Peripheral blood was collected after enrollment to separate plasma, and 13 blood coagulation related miRNAs were detected by the real-time quantitative polymerase chain reaction. All patents were followed up for 48 months, and the last follow-up date was 2018/12/31. MACCEs occurred during the follow up were documented, and MACCE-free survival was calculated. RESULTS MACCE incidence at 1 year, 2 year, 3 year and 4 year was 2.5, 6.1, 9.1 and 13.1% respectively, and mean MACCE-free survival was 45.2 (95% CI 44.0-46.4) months. Kaplan-Meier curves showed that miR-30e-5p, miR-92a-3p, miR-106a-5p and miR-126-5p high expressions were associated with longer MACCE-survival, while miR-423-5p high expression correlated with shorter MACCE-free survival. Multivariate Cox's regression analysis disclosed that miR-92a-3p, miR-126-5p and miR-652-3p independently predicted longer MACCE-free survival, while miR-423-5p independently predicted reduced MACCE-free survival in CAPD patients. CONCLUSION Circulating miR-92a-3p, miR-126-5p, miR-652-3p and miR-423-5p exhibit potential to serve as novel biomarkers for MACCE risk in patients undergoing CAPD.
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Xie J, Li Y, Liu X, Zhao Y, Li B, Ingvarsson PK, Zhang D. Evolutionary Origins of Pseudogenes and Their Association with Regulatory Sequences in Plants. THE PLANT CELL 2019; 31:563-578. [PMID: 30760562 PMCID: PMC6482637 DOI: 10.1105/tpc.18.00601] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 12/03/2018] [Accepted: 02/12/2019] [Indexed: 05/06/2023]
Abstract
Pseudogenes (Ψs), nonfunctional relatives of functional genes, form by duplication or retrotransposition, and loss of gene function by disabling mutations. Evolutionary analysis provides clues to Ψ origins and effects on gene regulation. However, few systematic studies of plant Ψs have been conducted, hampering comparative analyses. Here, we examined the origin, evolution, and expression patterns of Ψs and their relationships with noncoding sequences in seven angiosperm plants. We identified ∼250,000 Ψs, most of which are more lineage specific than protein-coding genes. The distribution of Ψs on the chromosome indicates that genome recombination may contribute to Ψ elimination. Most Ψs evolve rapidly in terms of sequence and expression levels, showing tissue- or stage-specific expression patterns. We found that a surprisingly large fraction of nontransposable element regulatory noncoding RNAs (microRNAs and long noncoding RNAs) originate from transcription of Ψ proximal upstream regions. We also found that transcription factor binding sites preferentially occur in putative Ψ proximal upstream regions compared with random intergenic regions, suggesting that Ψs have conditioned genome evolution by providing transcription factor binding sites that serve as promoters and enhancers. We therefore propose that rapid rewiring of Ψ transcriptional regulatory regions is a major mechanism driving the origin of novel regulatory modules.
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Affiliation(s)
- Jianbo Xie
- Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
- National Engineering Laboratory for Tree Breeding, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
- Key Laboratory of Genetics and Breeding in Forest Trees and Ornamental Plants, Ministry of Education, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
| | - Ying Li
- Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
- National Engineering Laboratory for Tree Breeding, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
- Key Laboratory of Genetics and Breeding in Forest Trees and Ornamental Plants, Ministry of Education, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
| | - Xiaomin Liu
- National Engineering Laboratory for Tree Breeding, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
- Key Laboratory of Genetics and Breeding in Forest Trees and Ornamental Plants, Ministry of Education, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
| | - Yiyang Zhao
- Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
- National Engineering Laboratory for Tree Breeding, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
- Key Laboratory of Genetics and Breeding in Forest Trees and Ornamental Plants, Ministry of Education, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
| | - Bailian Li
- Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
- National Engineering Laboratory for Tree Breeding, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
- Key Laboratory of Genetics and Breeding in Forest Trees and Ornamental Plants, Ministry of Education, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
- Department of Forestry, North Carolina State University, Raleigh, North Carolina 27695-8203
| | - Pär K Ingvarsson
- Linnean Center for Plant Biology, Department of Plant Biology, Swedish University of Agricultural Sciences, Box 7080, SE-750 07 Uppsala, Sweden
| | - Deqiang Zhang
- Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
- National Engineering Laboratory for Tree Breeding, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
- Key Laboratory of Genetics and Breeding in Forest Trees and Ornamental Plants, Ministry of Education, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, People's Republic of China
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Fathollahi A, Aslani S, Jamshidi A, Mahmoudi M. Epigenetics in osteoarthritis: Novel spotlight. J Cell Physiol 2019; 234:12309-12324. [DOI: 10.1002/jcp.28020] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 11/30/2018] [Indexed: 12/24/2022]
Affiliation(s)
- Anwar Fathollahi
- Department of Immunology School of Medicine, Shahid Beheshti University of Medical Sciences Tehran Iran
- Rheumatology Research Center, Tehran University of Medical Sciences Tehran Iran
| | - Saeed Aslani
- Rheumatology Research Center, Tehran University of Medical Sciences Tehran Iran
| | - Ahmadreza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Sciences Tehran Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences Tehran Iran
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