|
1
|
Li H, Meng J, Wang Z, Luan Y. PmiProPred: A novel method towards plant miRNA promoter prediction based on CNN-Transformer network and convolutional block attention mechanism. Int J Biol Macromol 2025; 302:140630. [PMID: 39909261 DOI: 10.1016/j.ijbiomac.2025.140630] [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: 09/23/2024] [Revised: 01/31/2025] [Accepted: 02/01/2025] [Indexed: 02/07/2025]
Abstract
It is crucial to understand the transcription mechanisms of miRNAs, especially considering the presence of peptides encoded by miRNAs. Since promoters function as the switch for gene transcription, precisely identifying these regions is essential for fully annotating miRNA transcripts. Nonetheless, existing computational methods still have room for improvement in the characterization of promoter regions. Here, we present PmiProPred, an advanced tool designed for predicting plant miRNA promoters from a wide spectrum of genomes. It consists of two core components: multi-stream deep feature extraction (MsDFE) and multi-stream deep feature refinement (MsDFR). The MsDFE utilizes Transformer and CNN to gather multi-view features, while the MsDFR focuses on aligning and refining them using channel and spatial attention mechanisms. Ultimately, a multi-layer perceptron is employed to accomplish the miRNA promoter identification task. Across three independent testing datasets, PmiProPred achieves accuracies of 94.630%, 96.659%, and 92.480%, respectively, substantially surpassing the latest methods. Additionally, PmiProPred is employed to identify potential core promoters in the upstream 2-kb regions of intergenic miRNAs in five plant species. We further conduct cis-regulatory elements mining on the predicted promoters and perform an in-depth analysis of the identified motifs. Altogether, PmiProPred is a robust and effective tool for discovering plant miRNA promoters.
Collapse
Affiliation(s)
- Haibin Li
- School of Computer Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China
| | - Jun Meng
- School of Computer Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China
| | - Zhaowei Wang
- School of Computer Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China
| | - Yushi Luan
- School of Bioengineering, Dalian University of Technology, Dalian, Liaoning 116024, China.
| |
Collapse
|
|
2
|
Vali R, Azadi A, Tizno A, Farkhondeh T, Samini F, Samarghandian S. miRNA contributes to neuropathic pains. Int J Biol Macromol 2023; 253:126893. [PMID: 37730007 DOI: 10.1016/j.ijbiomac.2023.126893] [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: 05/13/2023] [Revised: 08/29/2023] [Accepted: 09/11/2023] [Indexed: 09/22/2023]
Abstract
Neuropathic pain (NP) is a kind of chronic pain caused by direct injury to the peripheral or central nervous system (CNS). microRNAs (miRNAs) are small noncoding RNAs that mostly interact with the 3 untranslated region of messenger RNAs (mRNAs) to regulate the expression of multiple genes. NP is characterized by changes in the expression of receptors and mediators, and there is evidence that miRNAs may contribute to some of these alterations. In this review, we aimed to fully comprehend the connection between NP and miRNA; and also, to establish a link between neurology, biology, and dentistry. Studies have shown that targeting miRNAs may be an effective therapeutic strategy for the treatment of chronic pain and potential target for the prevention of NP.
Collapse
Affiliation(s)
- Reyhaneh Vali
- Department of Biology, Faculty of Modern Science, Tehran Medical Branch, Islamic Azad University, Tehran, Iran; Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Azadi
- Dental Research Center, Research Institute of Dental Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ashkan Tizno
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tahereh Farkhondeh
- Neuroscience Research Center, Kamyab Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fariborz Samini
- Department of Toxicology and Pharmacology, School of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran
| | - Saeed Samarghandian
- Department of Toxicology and Pharmacology, School of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran.
| |
Collapse
|
|
3
|
Ruan L, Lei J, Yuan Y, Li H, Yang H, Wang J, Zhang Q. MIR31HG, a potential lncRNA in human cancers and non-cancers. Front Genet 2023; 14:1145454. [PMID: 37636269 PMCID: PMC10449471 DOI: 10.3389/fgene.2023.1145454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 07/31/2023] [Indexed: 08/29/2023] Open
Abstract
Long non-coding RNAs have recently attracted considerable attention due to their aberrant expression in human diseases. LncMIR31HG is a novel lncRNA that is abnormally expressed in multiple diseases and implicated in various stages of disease progression. A large proportion of recent studies have indicated that MIR31HG has biological functions by triggering various signalling pathways in the pathogenesis of human diseases, especially cancers. More importantly, the abnormal expression of MIR31HG makes it a potential biomarker in diagnosis and prognosis, as well as a promising target for treatments. This review aims to systematically summarize the gene polymorphism, expression profiles, biological roles, underlying mechanisms, and clinical applications of MIR31HG in human diseases.
Collapse
Affiliation(s)
- Luxi Ruan
- Department of Oncology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jing Lei
- Department of Oncology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yihang Yuan
- Department of Oncology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Huizi Li
- Department of Oncology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hui Yang
- Department of Oncology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jinyan Wang
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Quanan Zhang
- Department of Oncology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| |
Collapse
|
|
4
|
MicroRNA expression is deregulated by aberrant methylation in B-cell acute lymphoblastic leukemia mouse model. Mol Biol Rep 2022; 49:1731-1739. [PMID: 35001247 DOI: 10.1007/s11033-021-06982-x] [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: 07/28/2021] [Accepted: 11/17/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND The expression of microRNAs (miRNAs) in the serum of B-cell acute lymphoblastic leukemia (B-ALL) patients is abnormal. Nevertheless, the underlying mechanism remains unclear. Recent studies indicate that the methylation state of circulating cell-free DNA (cfDNA) is different between cancer patients and healthy individuals. Therefore, we speculate that abnormal expression of miRNA may be associated with cfDNA methylation. METHODS A green fluorescent protein (GFP) labeled B-ALL transplantation animal model was established to explore the relationship between the miRNA expression and cfDNA methylation of the related gene. Quantitative real-time PCR (qRT-PCR) was used to detect the expression levels of miRNAs. Further, cfDNA methylation levels of the related genes were evaluated through bisulfite sequencing polymerase chain reaction (BSP). RESULTS The expression levels of miR-196b, miR-203, miR-34a-5p, miR-335-3p, miR-34b-5p, miR-615, miR-375-3p and miR-193b-5p in the serum of the model mice were significantly lower than those of the control group (P < 0.05). The methylation level of miR-196b promoter in cfDNA of the model group was significantly lower than that of the control group (P < 0.05), whereas no significant difference was noted in miR-203 promoter. The methylation levels of miR-196b and miR-203 coding region in cfDNA of the model group were significantly higher than those of the control group (P < 0.05). CONCLUSIONS These results showed that CpG island hypermethylation in the miRNA coding region of cfDNA is related to the low expression of miR-196b and miR-203.
Collapse
|
|
5
|
Hu M, Kuang R, Guo Y, Ma R, Hou Y, Xu Y, Qi X, Wang D, Zhou H, Xiong Y, Han X, Zhang J, Ruan J, Li X, Zhao S, Zhao Y, Xu X. Epigenomics analysis of miRNA cis-regulatory elements in pig muscle and fat tissues. Genomics 2022; 114:110276. [PMID: 35104610 DOI: 10.1016/j.ygeno.2022.110276] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 01/23/2022] [Accepted: 01/26/2022] [Indexed: 11/04/2022]
Abstract
Although large-scale and accurate identification of cis-regulatory elements on pig protein-coding and long non-coding genes has been reported, similar study on pig miRNAs is still lacking. Here, we systematically characterized the cis-regulatory elements of pig miRNAs in muscle and fat by adopting miRNAomes, ChIP-seq, ATAC-seq, RNA-seq and Hi-C data. In total, the cis-regulatory elements of 257 (85.95%) expressed miRNAs including 226 known and 31 novel miRNAs were identified. Especially, the miRNAs associated with super-enhancers, active promoters, and "A" compartment were significantly higher than those associated by typical enhancers, prompters without H3K27ac, and "B" compartment, respectively. The tissue specific transcription factors were the primary determination of core miRNA expression pattern in muscle and fat. Moreover, the miRNA promoters are more evolutionarily conserved than miRNA enhancers, like other type genes. Our study adds additional important information to existing pig epigenetic data and provides essential resource for future in-depth investigation of pig epigenetics.
Collapse
Affiliation(s)
- Mingyang Hu
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China
| | - Renzhuo Kuang
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China
| | - Yaping Guo
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China
| | - Ruixian Ma
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China
| | - Ye Hou
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China
| | - Yueyuan Xu
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China
| | - Xiaolong Qi
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China
| | - Daoyuan Wang
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China
| | - Honghong Zhou
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China
| | - Youcai Xiong
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China
| | - Xiaosong Han
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China
| | - Jinfu Zhang
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China
| | - Jinxue Ruan
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China
| | - Xinyun Li
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Shuhong Zhao
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
| | - Yunxia Zhao
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China.
| | - Xuewen Xu
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of the Ministry of Education and Key Laboratory of Swine Genetics and Breeding of Ministry of Agriculture, Huazhong Agricultural University, 430070 Wuhan, China; The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
| |
Collapse
|
|
6
|
Trigg NA, Skerrett-Byrne DA, Xavier MJ, Zhou W, Anderson AL, Stanger SJ, Katen AL, De Iuliis GN, Dun MD, Roman SD, Eamens AL, Nixon B. Acrylamide modulates the mouse epididymal proteome to drive alterations in the sperm small non-coding RNA profile and dysregulate embryo development. Cell Rep 2021; 37:109787. [PMID: 34610313 DOI: 10.1016/j.celrep.2021.109787] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 08/10/2021] [Accepted: 09/09/2021] [Indexed: 12/12/2022] Open
Abstract
Paternal exposure to environmental stressors elicits distinct changes to the sperm sncRNA profile, modifications that have significant post-fertilization consequences. Despite this knowledge, there remains limited mechanistic understanding of how paternal exposures modify the sperm sncRNA landscape. Here, we report the acute sensitivity of the sperm sncRNA profile to the reproductive toxicant acrylamide. Furthermore, we trace the differential accumulation of acrylamide-responsive sncRNAs to coincide with sperm transit of the proximal (caput) segment of the epididymis, wherein acrylamide exposure alters the abundance of several transcription factors implicated in the expression of acrylamide-sensitive sncRNAs. We also identify extracellular vesicles secreted from the caput epithelium in relaying altered sncRNA profiles to maturing spermatozoa and dysregulated gene expression during early embryonic development following fertilization by acrylamide-exposed spermatozoa. These data provide mechanistic links to account for how environmental insults can alter the sperm epigenome and compromise the transcriptomic profile of early embryos.
Collapse
Affiliation(s)
- Natalie A Trigg
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - David A Skerrett-Byrne
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Miguel J Xavier
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Wei Zhou
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia; Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, VIC 3052, Australia; Gynaecology Research Centre, The Royal Women's Hospital, Parkville, VIC 3052, Australia
| | - Amanda L Anderson
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Simone J Stanger
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Aimee L Katen
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia; Priority Research Centre for Drug Development, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia
| | - Geoffry N De Iuliis
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Matthew D Dun
- Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia; Priority Research Centre for Cancer Research Innovation and Translation, Hunter Medical Research Institute, Lambton, NSW 2305, Australia
| | - Shaun D Roman
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia; Priority Research Centre for Drug Development, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia
| | - Andrew L Eamens
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Brett Nixon
- Priority Research Centre for Reproductive Science, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia.
| |
Collapse
|
|
7
|
Zhou Y, Yue Y, Fan S, Jia Q, Ding X. Advances in Pathophysiology of Triple-Negative Breast Cancer: The Potential of lncRNAs for Clinical Diagnosis, Treatment, and Prognostic Monitoring. Mol Biotechnol 2021; 63:1093-1102. [PMID: 34245439 DOI: 10.1007/s12033-021-00368-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 07/03/2021] [Indexed: 12/12/2022]
Abstract
Recent studies have shown that long non-coding RNAs (lncRNAs) are involved in several gene expression regulation processes, including epigenetic regulation, transcriptional regulation, post-transcriptional regulation, and translation regulation. It also plays a crucial role in the regulation of several characteristics of cancer biology, and the dysregulation of lncRNA expression in cancer may be part of the cause of cancer progression. Meanwhile, more and more studies are trying to determine the association between lncRNA expression and TNBC, as well as the functional role and molecular mechanism of the abnormally expressed lncRNA. Therefore, this review lists some abnormal lncRNAs in TNBC, further analyzes their molecular mechanisms and biological roles in the development of TNBC, and summarizes the potential of lncRNAs as biomarkers and therapeutic targets of TNBC, so as to provide ideas for clinical diagnosis, targeted therapy, and prognosis monitoring of TNBC.
Collapse
Affiliation(s)
- Yangkun Zhou
- School of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China
| | - Yang Yue
- School of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China
| | - Siyu Fan
- School of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China
| | - Qiaojun Jia
- School of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China
| | - Xianfeng Ding
- School of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, China.
| |
Collapse
|
|
8
|
Sheinboim D, Parikh S, Parikh R, Menuchin A, Shapira G, Kapitansky O, Elkoshi N, Ruppo S, Shaham L, Golan T, Elgavish S, Nevo Y, Bell RE, Malcov H, Shomron N, Taub JW, Izraeli S, Levy C. Slow transcription of the 99a/let-7c/125b-2 cluster results in differential miRNA expression and promotes melanoma phenotypic plasticity. J Invest Dermatol 2021; 141:2944-2956.e6. [PMID: 34186058 DOI: 10.1016/j.jid.2021.03.036] [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: 11/09/2020] [Revised: 03/21/2021] [Accepted: 03/31/2021] [Indexed: 10/21/2022]
Abstract
Almost half of human miRNAs are encoded in clusters. Although transcribed as a single unit, the levels of individual mature miRNAs often differ. The mechanisms underlying differential biogenesis of clustered miRNAs and the resulting physiological implications are mostly unknown. Here, we report that the melanoma master transcription regulator MITF regulates the differential expression of the 99a/let-7c/125b-2 cluster by altering the distribution of RNA polymerase II (Pol-II) along the cluster. We discovered that MITF interacts with TRIM28, a known inhibitor of Pol-II transcription elongation, at the let-7c region resulting in Pol-II pausing and causing its elevated expression, whereas low levels of Pol-II occupation over miR-99a and miR-125b-2 regions decreases their biogenesis. Furthermore, we showed that this differential expression affects the phenotypic state of melanoma cells. RNA-seq analysis of proliferative melanoma cells that express miR-99a and miR-125b mimics revealed a transcriptomic shift toward an invasive phenotype. Conversely, expression of a let-7c mimic in invasive melanoma cells induced a shift to a more proliferative state. We confirmed direct target genes of these miRNAs: FGFR3, BAP1, Bcl2, TGFBR1, and CDKN1A. Our study demonstrates a MITF-governed biogenesis mechanism that results in differential expression of clustered 99a/let-7c/125b-2 miRNAs that control melanoma progression.
Collapse
Affiliation(s)
- Danna Sheinboim
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Shivang Parikh
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Roma Parikh
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Amitai Menuchin
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Guy Shapira
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Oxana Kapitansky
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Nadav Elkoshi
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Shmuel Ruppo
- Info-CORE, Bioinformatics Unit of the I-CORE, Hebrew University of Jerusalem and Hadassah Medical Center, Jerusalem 9112102, Israel
| | - Lital Shaham
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Division of Pediatric Hematology-Oncology Department, Schneider Children's Medical Center, Petah Tikva 49202, Israel
| | - Tamar Golan
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Sharona Elgavish
- Info-CORE, Bioinformatics Unit of the I-CORE, Hebrew University of Jerusalem and Hadassah Medical Center, Jerusalem 9112102, Israel
| | - Yuval Nevo
- Info-CORE, Bioinformatics Unit of the I-CORE, Hebrew University of Jerusalem and Hadassah Medical Center, Jerusalem 9112102, Israel
| | - Rachel E Bell
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Hagar Malcov
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Noam Shomron
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Edmond J. Safra Center of Bioinformatics, Tel Aviv University, Tel Aviv 69978, Israel
| | - Jeffrey W Taub
- Wayne State University School of Medicine, Detroit, MI 48201, USA; Division of Pediatric Hematology and Oncology, Children's Hospital of Michigan, Detroit, MI 48201, USA
| | - Shai Izraeli
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Info-CORE, Bioinformatics Unit of the I-CORE, Hebrew University of Jerusalem and Hadassah Medical Center, Jerusalem 9112102, Israel
| | - Carmit Levy
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
| |
Collapse
|
|
9
|
Veryaskina YA, Titov SE, Kovynev IB, Fedorova SS, Pospelova TI, Zhimulev IF. MicroRNAs in the Myelodysplastic Syndrome. Acta Naturae 2021; 13:4-15. [PMID: 34377552 PMCID: PMC8327150 DOI: 10.32607/actanaturae.11209] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 12/15/2020] [Indexed: 12/20/2022] Open
Abstract
The myelodysplastic syndrome (MDS) holds a special place among blood cancers, as it represents a whole spectrum of hematological disorders with impaired differentiation of hematopoietic precursors, bone marrow dysplasia, genetic instability and is noted for an increased risk of acute myeloid leukemia. Both genetic and epigenetic factors, including microRNAs (miRNAs), are involved in MDS development. MicroRNAs are short non-coding RNAs that are important regulators of normal hematopoiesis, and abnormal changes in their expression levels can contribute to hematological tumor development. To assess the prognosis of the disease, an international assessment system taking into account a karyotype, the number of blast cells, and the degree of deficiency of different blood cell types is used. However, the overall survival and effectiveness of the therapy offered are not always consistent with predictions. The search for new biomarkers, followed by their integration into the existing prognostic system, will allow for personalized treatment to be performed with more precision. Additionally, this paper explains how miRNA expression levels correlate with the prognosis of overall survival and response to the therapy offered.
Collapse
Affiliation(s)
- Y. A. Veryaskina
- Institute of Cytology and Genetics, SB RAS, Novosibirsk, 630090 Russia
- Institute of Molecular and Cellular Biology, SB RAS, Novosibirsk, 630090 Russia
| | - S. E. Titov
- Institute of Molecular and Cellular Biology, SB RAS, Novosibirsk, 630090 Russia
- Vector-Best, Novosibirsk, 630117 Russia
| | - I. B. Kovynev
- Novosibirsk State Medical University, Novosibirsk, 630091 Russia
| | - S. S. Fedorova
- Novosibirsk State Medical University, Novosibirsk, 630091 Russia
| | - T. I. Pospelova
- Novosibirsk State Medical University, Novosibirsk, 630091 Russia
| | - I. F. Zhimulev
- Institute of Molecular and Cellular Biology, SB RAS, Novosibirsk, 630090 Russia
| |
Collapse
|
|
10
|
Kwok ZH, Zhang B, Chew XH, Chan JJ, Teh V, Yang H, Kappei D, Tay Y. Systematic Analysis of Intronic miRNAs Reveals Cooperativity within the Multicomponent FTX Locus to Promote Colon Cancer Development. Cancer Res 2020; 81:1308-1320. [PMID: 33172934 DOI: 10.1158/0008-5472.can-20-1406] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 10/05/2020] [Accepted: 11/06/2020] [Indexed: 11/16/2022]
Abstract
Approximately half of all miRNA reside within intronic regions and are often cotranscribed with their host genes. However, most studies of intronic miRNA focus on individual miRNA, while conversely most studies of protein-coding and noncoding genes frequently ignore any intron-derived miRNA. We hypothesize that the individual components of such multigenic loci may play cooperative or competing roles in driving disease progression and that examining the combinatorial effect of these components would uncover deeper insights into their functional importance. To address this, we performed systematic analyses of intronic miRNA:host loci in colon cancer. The FTX locus, comprising of a long noncoding RNA FTX and multiple intronic miRNA, was highly upregulated in cancer, and cooperativity within this multicomponent locus promoted cancer growth. FTX interacted with DHX9 and DICER and regulated A-to-I RNA editing and miRNA expression. These results show for the first time that a long noncoding RNA can regulate A-to-I RNA editing, further expanding the functional repertoire of long noncoding RNA. Intronic miR-374b and miR-545 inhibited tumor suppressors PTEN and RIG-I to enhance proto-oncogenic PI3K-AKT signaling. Furthermore, intronic miR-421 may exert an autoregulatory effect on miR-374b and miR-545. Taken together, our data unveil the intricate interplay between intronic miRNA and their host transcripts in the modulation of key signaling pathways and disease progression, adding new perspectives to the functional landscape of multigenic loci. SIGNIFICANCE: This study illustrates the functional relationships between individual components of multigenic loci in regulating cancer progression.See related commentary by Calin, p. 1212.
Collapse
Affiliation(s)
- Zhi Hao Kwok
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Bin Zhang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Xiao Hong Chew
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Jia Jia Chan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Velda Teh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Henry Yang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Dennis Kappei
- Cancer Science Institute of Singapore, National University of Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yvonne Tay
- Cancer Science Institute of Singapore, National University of Singapore, Singapore. .,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| |
Collapse
|
|
11
|
Saha PK, Hamilton MP, Rajapakshe K, Putluri V, Felix JB, Masschelin P, Cox AR, Bajaj M, Putluri N, Coarfa C, Hartig SM. miR-30a targets gene networks that promote browning of human and mouse adipocytes. Am J Physiol Endocrinol Metab 2020; 319:E667-E677. [PMID: 32799658 PMCID: PMC7864240 DOI: 10.1152/ajpendo.00045.2020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
MicroRNA-30a (miR-30a) impacts adipocyte function, and its expression in white adipose tissue (WAT) correlates with insulin sensitivity in obesity. Bioinformatic analysis demonstrates that miR-30a expression contributes to 2% of all miRNA expression in human tissues. However, molecular mechanisms of miR-30a function in fat cells remain unclear. Here, we expanded our understanding of how miR-30a expression contributes to antidiabetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist activity and metabolic functions in adipocytes. We found that WAT isolated from diabetic patients shows reduced miR-30a levels and diminished expression of the canonical PPARγ target genes ADIPOQ and FABP4 relative to lean counterparts. In human adipocytes, miR-30a required PPARγ for maximal expression, and the PPARγ agonist rosiglitazone robustly induced miR-30a but not other miR-30 family members. Transcriptional activity studies in human adipocytes also revealed that ectopic expression of miR-30a enhanced the activity of rosiglitazone coupled with higher expression of fatty acid and glucose metabolism markers. Diabetic mice that overexpress ectopic miR-30a in subcutaneous WAT display durable reductions in serum glucose and insulin levels for more than 30 days. In agreement with our in vitro findings, RNA-seq coupled with Gene Set Enrichment Analysis (GSEA) suggested that miR-30a enabled activation of the beige fat program in vivo, as evidenced by enhanced mitochondrial biogenesis and induction of UCP1 expression. Metabolomic and gene expression profiling established that the long-term effects of ectopic miR-30a expression enable accelerated glucose metabolism coupled with subcutaneous WAT hyperplasia. Together, we establish a putative role of miR-30a in mediating PPARγ activity and advancing metabolic programs of white to beige fat conversion.
Collapse
Affiliation(s)
- Pradip K Saha
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Mark P Hamilton
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Kimal Rajapakshe
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Vasanta Putluri
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Jessica B Felix
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Peter Masschelin
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Aaron R Cox
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Mandeep Bajaj
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Nagireddy Putluri
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Cristian Coarfa
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Sean M Hartig
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| |
Collapse
|
|
12
|
Islam ABMMK, Mohammad E, Khan MAAK. Aberration of the modulatory functions of intronic microRNA hsa-miR-933 on its host gene ATF2 results in type II diabetes mellitus and neurodegenerative disease development. Hum Genomics 2020; 14:34. [PMID: 32993798 PMCID: PMC7526404 DOI: 10.1186/s40246-020-00285-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 09/01/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND MicroRNAs are ~ 22-nucleotide-long biological modifiers that act as the post-transcriptional modulator of gene expression. Some of them are identified to be embedded within the introns of protein-coding genes, these miRNAs are called the intronic miRNAs. Previous findings state that these intronic miRNAs are co-expressed with their host genes. This co-expression is necessary to maintain the robustness of the biological system. Till to date, only a few experiments are performed discretely to elucidate the functional relationship between few co-expressed intronic miRNAs and their associated host genes. RESULTS In this study, we have interpreted the underlying modulatory mechanisms of intronic miRNA hsa-miR-933 on its target host gene ATF2 and found that aberration can lead to several disease conditions. A protein-protein interaction network-based approach was adopted, and functional enrichment analysis was performed to elucidate the significantly over-represented biological functions and pathways of the common targets. Our approach delineated that hsa-miR-933 might control the hyperglycemic condition and hyperinsulinism by regulating ATF2 target genes MAP4K4, PRKCE, PEA15, BDNF, PRKACB, and GNAS which can otherwise lead to the development of type II diabetes mellitus. Moreover, we showed that hsa-miR-933 can regulate a target of ATF2, brain-derived neurotrophic factor (BDNF), to modulate the optimal expression of ATF2 in neuron cells to render neuroprotection for the inhibition of neurodegenerative diseases. CONCLUSIONS Our in silico model provides interesting resources for experimentations in a model organism or cell line for further validation. These findings may extend the common perception of gene expression analysis with new regulatory functionality.
Collapse
Affiliation(s)
| | - Eusra Mohammad
- Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh
- Current Affiliation: Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
| | - Md. Abdullah-Al-Kamran Khan
- Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, Bangladesh
- Current Affiliation: Department of Mathematics and Natural Sciences, BRAC University, Dhaka, Bangladesh
| |
Collapse
|
|
13
|
Capaci V, Bascetta L, Fantuz M, Beznoussenko GV, Sommaggio R, Cancila V, Bisso A, Campaner E, Mironov AA, Wiśniewski JR, Ulloa Severino L, Scaini D, Bossi F, Lees J, Alon N, Brunga L, Malkin D, Piazza S, Collavin L, Rosato A, Bicciato S, Tripodo C, Mantovani F, Del Sal G. Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome. Nat Commun 2020; 11:3945. [PMID: 32770028 PMCID: PMC7414119 DOI: 10.1038/s41467-020-17596-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 07/03/2020] [Indexed: 12/16/2022] Open
Abstract
TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1α, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading to enhanced vesicular trafficking and secretion. The mut-p53/HIF1α/miR-30d axis potentiates the release of soluble factors and the deposition and remodeling of the ECM, affecting mechano-signaling and stromal cells activation within the tumor microenvironment, thereby enhancing tumor growth and metastatic colonization.
Collapse
Affiliation(s)
- Valeria Capaci
- Laboratorio Nazionale CIB (LNCIB), 34149, Trieste, Italy
| | - Lorenzo Bascetta
- Laboratorio Nazionale CIB (LNCIB), 34149, Trieste, Italy
- International School for Advanced Studies (SISSA), 34146, Trieste, Italy
| | - Marco Fantuz
- Laboratorio Nazionale CIB (LNCIB), 34149, Trieste, Italy
- International School for Advanced Studies (SISSA), 34146, Trieste, Italy
| | | | | | - Valeria Cancila
- Tumor Immunology Unit, Department of Health Science, Human Pathology Section, University of Palermo, School of Medicine, 90133, Palermo, Italy
| | - Andrea Bisso
- Laboratorio Nazionale CIB (LNCIB), 34149, Trieste, Italy
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy
| | - Elena Campaner
- Laboratorio Nazionale CIB (LNCIB), 34149, Trieste, Italy
- Dipartimento di Scienze della Vita, Università degli Studi di Trieste, 34127, Trieste, Italy
| | - Alexander A Mironov
- Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139, Milan, Italy
| | - Jacek R Wiśniewski
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 85152, Martinsried, Germany
| | - Luisa Ulloa Severino
- Dipartimento di Scienze della Vita, Università degli Studi di Trieste, 34127, Trieste, Italy
| | - Denis Scaini
- International School for Advanced Studies (SISSA), 34146, Trieste, Italy
| | - Fleur Bossi
- Dipartimento di Scienze della Vita, Università degli Studi di Trieste, 34127, Trieste, Italy
| | - Jodi Lees
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Noa Alon
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Ledia Brunga
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - David Malkin
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Silvano Piazza
- Laboratorio Nazionale CIB (LNCIB), 34149, Trieste, Italy
| | - Licio Collavin
- Laboratorio Nazionale CIB (LNCIB), 34149, Trieste, Italy
- Dipartimento di Scienze della Vita, Università degli Studi di Trieste, 34127, Trieste, Italy
| | - Antonio Rosato
- Veneto Institute of Oncology IOV-IRCCS, 35128, Padua, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128, Padova, Italy
| | - Silvio Bicciato
- Center for Genome Research, University of Modena and Reggio Emilia, 41125, Modena, Italy
| | - Claudio Tripodo
- Tumor Immunology Unit, Department of Health Science, Human Pathology Section, University of Palermo, School of Medicine, 90133, Palermo, Italy
| | - Fiamma Mantovani
- Laboratorio Nazionale CIB (LNCIB), 34149, Trieste, Italy
- Dipartimento di Scienze della Vita, Università degli Studi di Trieste, 34127, Trieste, Italy
| | - Giannino Del Sal
- Laboratorio Nazionale CIB (LNCIB), 34149, Trieste, Italy.
- Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139, Milan, Italy.
- Dipartimento di Scienze della Vita, Università degli Studi di Trieste, 34127, Trieste, Italy.
| |
Collapse
|
|
14
|
Kang L, Han C, Yang G, Li H, Li T, Yang S, Liang N, Zhong R, Jia L, Zhu D, Zhang Y. miR-378 and its host gene Ppargc1β exhibit independent expression in mouse skeletal muscle. Acta Biochim Biophys Sin (Shanghai) 2020; 52:883-890. [PMID: 32602911 DOI: 10.1093/abbs/gmaa061] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 03/12/2020] [Accepted: 03/29/2020] [Indexed: 12/28/2022] Open
Abstract
MicroRNAs (miRNAs) are implicated in multiple biological processes in physiological and pathological settings. Nearly half of the known miRNAs are classified as 'intronic' miRNAs because they are embedded within the introns of protein-coding or noncoding genes. Such miRNAs were thought to be processed from primary host gene transcripts and share the promoter of their host. Recent analyses predicted that some intronic miRNAs might be transcribed and regulated as independent units, but there is little direct evidence for this in a specific biological context. Here, we focused on miR-378, which is located within the first intron of the peroxisome proliferator-activated receptor γ coactivator 1-beta (Ppargc1β) gene and critically regulates skeletal muscle cell differentiation and muscle regeneration. We demonstrate that miR-378 and Ppargc1β exhibit distinct expression patterns during skeletal muscle cell differentiation. In terminally differentiated adult skeletal muscle tissues of mice, miR-378 is predominantly expressed in glycolytic muscle, whereas Ppargc1β is mainly expressed in oxidative soleus muscle. Mechanistically, miR-378, but not Ppargc1β, is regulated by the transcription factor, MyoD, in muscle cells. Our findings identify a regulatory model of miR-378 expression, thereby helping us to understand its physiological function in skeletal muscle.
Collapse
Affiliation(s)
- Lin Kang
- Department of Endocrinology, the Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Chunmiao Han
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
| | - Guangyan Yang
- Department of Endocrinology, the Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Hu Li
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
| | - Tingting Li
- Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Shu Yang
- Department of Endocrinology, the Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Na Liang
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
| | - Ran Zhong
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
| | - Lijing Jia
- Department of Endocrinology, the Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China
| | - Dahai Zhu
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510530, China
| | - Yong Zhang
- The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China
| |
Collapse
|
|
15
|
Pidíkova P, Reis R, Herichova I. miRNA Clusters with Down-Regulated Expression in Human Colorectal Cancer and Their Regulation. Int J Mol Sci 2020; 21:E4633. [PMID: 32610706 PMCID: PMC7369991 DOI: 10.3390/ijms21134633] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/24/2020] [Accepted: 06/27/2020] [Indexed: 02/07/2023] Open
Abstract
Regulation of microRNA (miRNA) expression has been extensively studied with respect to colorectal cancer (CRC), since CRC is one of the leading causes of cancer mortality worldwide. Transcriptional control of miRNAs creating clusters can be, to some extent, estimated from cluster position on a chromosome. Levels of miRNAs are also controlled by miRNAs "sponging" by long non-coding RNAs (ncRNAs). Both types of miRNA regulation strongly influence their function. We focused on clusters of miRNAs found to be down-regulated in CRC, containing miR-1, let-7, miR-15, miR-16, miR-99, miR-100, miR-125, miR-133, miR-143, miR-145, miR-192, miR-194, miR-195, miR-206, miR-215, miR-302, miR-367 and miR-497 and analysed their genome position, regulation and functions. Only evidence provided with the use of CRC in vivo and/or in vitro models was taken into consideration. Comprehensive research revealed that down-regulated miRNA clusters in CRC are mostly located in a gene intron and, in a majority of cases, miRNA clusters possess cluster-specific transcriptional regulation. For all selected clusters, regulation mediated by long ncRNA was experimentally demonstrated in CRC, at least in one cluster member. Oncostatic functions were predominantly linked with the reviewed miRNAs, and their high expression was usually associated with better survival. These findings implicate the potential of down-regulated clusters in CRC to become promising multi-targets for therapeutic manipulation.
Collapse
Affiliation(s)
- Paulína Pidíkova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia;
| | - Richard Reis
- First Surgery Department, University Hospital, Comenius University in Bratislava, 811 07 Bratislava, Slovakia;
| | - Iveta Herichova
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University in Bratislava, 842 15 Bratislava, Slovakia;
| |
Collapse
|
|
16
|
Wierzbinska JA, Toth R, Ishaque N, Rippe K, Mallm JP, Klett LC, Mertens D, Zenz T, Hielscher T, Seifert M, Küppers R, Assenov Y, Lutsik P, Stilgenbauer S, Roessner PM, Seiffert M, Byrd J, Oakes CC, Plass C, Lipka DB. Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL. Genome Med 2020; 12:29. [PMID: 32188505 PMCID: PMC7081711 DOI: 10.1186/s13073-020-00724-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 02/11/2020] [Indexed: 02/07/2023] Open
Abstract
Background In cancer, normal epigenetic patterns are disturbed and contribute to gene expression changes, disease onset, and progression. The cancer epigenome is composed of the epigenetic patterns present in the tumor-initiating cell at the time of transformation, and the tumor-specific epigenetic alterations that are acquired during tumor initiation and progression. The precise dissection of these two components of the tumor epigenome will facilitate a better understanding of the biological mechanisms underlying malignant transformation. Chronic lymphocytic leukemia (CLL) originates from differentiating B cells, which undergo extensive epigenetic programming. This poses the challenge to precisely determine the epigenomic ground state of the cell-of-origin in order to identify CLL-specific epigenetic aberrations. Methods We developed a linear regression model, methylome-based cell-of-origin modeling (Methyl-COOM), to map the cell-of-origin for individual CLL patients based on the continuum of epigenomic changes during normal B cell differentiation. Results Methyl-COOM accurately maps the cell-of-origin of CLL and identifies CLL-specific aberrant DNA methylation events that are not confounded by physiologic epigenetic B cell programming. Furthermore, Methyl-COOM unmasks abnormal action of transcription factors, altered super-enhancer activities, and aberrant transcript expression in CLL. Among the aberrantly regulated transcripts were many genes that have previously been implicated in T cell biology. Flow cytometry analysis of these markers confirmed their aberrant expression on malignant B cells at the protein level. Conclusions Methyl-COOM analysis of CLL identified disease-specific aberrant gene regulation. The aberrantly expressed genes identified in this study might play a role in immune-evasion in CLL and might serve as novel targets for immunotherapy approaches. In summary, we propose a novel framework for in silico modeling of reference DNA methylomes and for the identification of cancer-specific epigenetic changes, a concept that can be broadly applied to other human malignancies. Electronic supplementary material Supplementary information accompanies this paper at 10.1186/s13073-020-00724-7.
Collapse
Affiliation(s)
- Justyna A Wierzbinska
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.,The German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Reka Toth
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Naveed Ishaque
- The German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Karsten Rippe
- The German Cancer Consortium (DKTK), Heidelberg, Germany.,Division of Chromatin Networks, DKFZ, Heidelberg, Germany
| | - Jan-Philipp Mallm
- The German Cancer Consortium (DKTK), Heidelberg, Germany.,Division of Chromatin Networks, DKFZ, Heidelberg, Germany
| | - Lara C Klett
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.,Division of Chromatin Networks, DKFZ, Heidelberg, Germany
| | - Daniel Mertens
- The German Cancer Consortium (DKTK), Heidelberg, Germany.,Mechanisms of Leukemogenesis, DKFZ, Heidelberg, Germany
| | - Thorsten Zenz
- Experimental Hematology Lab, University Hospital Zurich, Zurich, Switzerland
| | | | - Marc Seifert
- Group Molecular Genetics, Essen University Hospital, Essen, Germany
| | - Ralf Küppers
- Group Molecular Genetics, Essen University Hospital, Essen, Germany
| | - Yassen Assenov
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Pavlo Lutsik
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | | | | | | | - John Byrd
- Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, USA
| | - Christopher C Oakes
- Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, USA.,Department of Biomedical Informatics, The Ohio State University, Columbus, USA
| | - Christoph Plass
- Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. .,The German Cancer Consortium (DKTK), Heidelberg, Germany.
| | - Daniel B Lipka
- The German Cancer Consortium (DKTK), Heidelberg, Germany. .,Section Translational Cancer Epigenomics, Division of Translational Medical Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany. .,National Center for Tumor Diseases (NCT), Heidelberg, Germany. .,Faculty of Medicine, Medical Center, Otto-von-Guericke-University, 39120, Magdeburg, Germany.
| |
Collapse
|
|
17
|
Zaporozhchenko IA, Rykova EY, Laktionov PP. The Fundamentals of miRNA Biology: Structure, Biogenesis, and Regulatory Functions. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2020. [DOI: 10.1134/s106816202001015x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
|
|
18
|
Wang S, Talukder A, Cha M, Li X, Hu H. Computational annotation of miRNA transcription start sites. Brief Bioinform 2020; 22:380-392. [PMID: 32003428 PMCID: PMC7820843 DOI: 10.1093/bib/bbz178] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 12/13/2019] [Accepted: 12/29/2019] [Indexed: 12/26/2022] Open
Abstract
Motivation MicroRNAs (miRNAs) are small noncoding RNAs that play important roles in gene regulation and phenotype development. The identification of miRNA transcription start sites (TSSs) is critical to understand the functional roles of miRNA genes and their transcriptional regulation. Unlike protein-coding genes, miRNA TSSs are not directly detectable from conventional RNA-Seq experiments due to miRNA-specific process of biogenesis. In the past decade, large-scale genome-wide TSS-Seq and transcription activation marker profiling data have become available, based on which, many computational methods have been developed. These methods have greatly advanced genome-wide miRNA TSS annotation. Results In this study, we summarized recent computational methods and their results on miRNA TSS annotation. We collected and performed a comparative analysis of miRNA TSS annotations from 14 representative studies. We further compiled a robust set of miRNA TSSs (RSmirT) that are supported by multiple studies. Integrative genomic and epigenomic data analysis on RSmirT revealed the genomic and epigenomic features of miRNA TSSs as well as their relations to protein-coding and long non-coding genes. Contact xiaoman@mail.ucf.edu, haihu@cs.ucf.edu
Collapse
Affiliation(s)
- Saidi Wang
- Computer Science, University of Central Florida, Orlando, FL-32816, US
| | - Amlan Talukder
- Computer Science, University of Central Florida, Orlando, FL-32816, US
| | - Mingyu Cha
- Computer Science, University of Central Florida, Orlando, FL-32816, US
| | - Xiaoman Li
- Burnett School of Biomedical Science, University of Central Florida, Orlando, FL-32816, US
| | - Haiyan Hu
- Computer Science, University of Central Florida, Orlando, FL-32816, US
| |
Collapse
|
|
19
|
The Transcribed-Ultra Conserved Regions: Novel Non-Coding RNA Players in Neuroblastoma Progression. Noncoding RNA 2019; 5:ncrna5020039. [PMID: 31167408 PMCID: PMC6631508 DOI: 10.3390/ncrna5020039] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/30/2019] [Accepted: 06/03/2019] [Indexed: 12/15/2022] Open
Abstract
The Transcribed-Ultra Conserved Regions (T-UCRs) are a class of novel non-coding RNAs that arise from the dark matter of the genome. T-UCRs are highly conserved between mouse, rat, and human genomes, which might indicate a definitive role for these elements in health and disease. The growing body of evidence suggests that T-UCRs contribute to oncogenic pathways. Neuroblastoma is a type of childhood cancer that is challenging to treat. The role of non-coding RNAs in the pathogenesis of neuroblastoma, in particular for cancer development, progression, and therapy resistance, has been documented. Exosmic non-coding RNAs are also involved in shaping the biology of the tumor microenvironment in neuroblastoma. In recent years, the involvement of T-UCRs in a wide variety of pathways in neuroblastoma has been discovered. Here, we present an overview of the involvement of T-UCRs in various cellular pathways, such as DNA damage response, proliferation, chemotherapy response, MYCN (v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (avian)) amplification, gene copy number, and immune response, as well as correlate it to patient survival in neuroblastoma.
Collapse
|
|
20
|
Non-Coding RNAs as New Therapeutic Targets in the Context of Renal Fibrosis. Int J Mol Sci 2019; 20:ijms20081977. [PMID: 31018516 PMCID: PMC6515288 DOI: 10.3390/ijms20081977] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 04/19/2019] [Accepted: 04/20/2019] [Indexed: 12/15/2022] Open
Abstract
Fibrosis, or tissue scarring, is defined as the excessive, persistent and destructive accumulation of extracellular matrix components in response to chronic tissue injury. Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to the progressive and irreversible decline in kidney function. Limited therapeutic options are available and the molecular mechanisms governing the renal fibrosis process are complex and remain poorly understood. Recently, the role of non-coding RNAs, and in particular microRNAs (miRNAs), has been described in kidney fibrosis. Seminal studies have highlighted their potential importance as new therapeutic targets and innovative diagnostic and/or prognostic biomarkers. This review will summarize recent scientific advances and will discuss potential clinical applications as well as future research directions.
Collapse
|
|
21
|
Wang JK, Wang Z, Li G. MicroRNA-125 in immunity and cancer. Cancer Lett 2019; 454:134-145. [PMID: 30981762 DOI: 10.1016/j.canlet.2019.04.015] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/09/2019] [Accepted: 04/09/2019] [Indexed: 12/31/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that play a wide variety of critical roles in different biological processes by post-transcriptionally regulating gene expression. They access diverse regulatory pathways during various stages of cellular differentiation, growth, and apoptosis, and can contribute to both normal and diseased functions. One important family of miRNAs involved in these functions is the miR-125 family (miR-125a and miR-125b). Investigations have been made to increasingly uncover the mechanisms by which the miR-125 family regulates normal homeostasis and growth in a variety of cell types including immune cells, and how dysregulation of miR-125a and miR-125b can lead to disease pathogenesis and tumorigenesis. In this review, we summarize what is currently known about miR-125a and miR-125b, mainly focusing on their roles in immune cell development and function as well as tumor suppression and promotion.
Collapse
Affiliation(s)
- Jessica K Wang
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, United States
| | - Zhe Wang
- Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China; Suzhou Institute of Systems Medicine, Suzhou, 215123, China
| | - Guideng Li
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, United States; Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China; Suzhou Institute of Systems Medicine, Suzhou, 215123, China.
| |
Collapse
|
|
22
|
Du H, Chen Y. Competing endogenous RNA networks in cervical cancer: function, mechanism and perspective. J Drug Target 2019; 27:709-723. [PMID: 30052083 DOI: 10.1080/1061186x.2018.1505894] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In the past several years, competing endogenous RNAs (ceRNAs) have emerged as a potential class of post-transcriptional regulators that alter gene expression through a microRNA (miRNA)-mediated mechanism. An increasing number of studies have found that ceRNAs play important roles in tumorigenesis. Cervical cancer is one of the most common cancers in female malignancies. Despite advances in our understanding of this neoplasm, patients with advanced cervical cancer still have poor prognosis. There is an urgent need to provide a new insight on the mechanism of cervical cancer development and may be acted as new anticancer therapeutic strategies. Here, we review the ceRNA studies and coherent researches in cervical cancer, especially in long non-coding RNA (lncRNA) and miRNAs in order to broaden horizons into mechanisms, selection biomarkers for diagnosis as well as predicting prognosis, and targeting treatment for cervical cancer in the future.
Collapse
Affiliation(s)
- Hui Du
- a Department of Obstetrics and Gynecology , The Second Hospital of Hebei Medical University , Shijiazhuang , China
| | - Ying Chen
- b Department of Gynecologic Oncology , Tianjin Medical University Cancer Institute and Hospital , Tianjin , China.,c Key Laboratory of Cancer Prevention and Therapy , Tianjin , China.,d National Clinical Research Centre of Cancer , Tianjin , China
| |
Collapse
|
|
23
|
Milevskiy MJG, Gujral U, Del Lama Marques C, Stone A, Northwood K, Burke LJ, Gee JMW, Nephew K, Clark S, Brown MA. MicroRNA-196a is regulated by ER and is a prognostic biomarker in ER+ breast cancer. Br J Cancer 2019; 120:621-632. [PMID: 30783203 PMCID: PMC6461839 DOI: 10.1038/s41416-019-0395-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 12/16/2018] [Accepted: 01/15/2019] [Indexed: 12/18/2022] Open
Abstract
Background MicroRNAs are potent post-transcriptional regulators involved in all hallmarks of cancer. Mir-196a is transcribed from two loci and has been implicated in a wide range of developmental and pathogenic processes, with targets including Hox, Fox, Cdk inhibitors and annexins. Genetic variants and altered expression of MIR196A are associated with risk and progression of multiple cancers including breast cancer, however little is known about the regulation of the genes encoding this miRNA, nor the impact of variants therein. Methods Genomic data and chromatin interaction analysis were used to discover functional promoter and enhancer elements for MIR196A. Expression data were used to associate MIR196A with mechanisms of resistance, breast cancer subtypes and prognosis. Results Here we demonstrate that MIR196A displays complex and dynamic expression patterns, in part controlled by long-range transcriptional regulation between promoter and enhancer elements bound by ERα. Expression of this miRNA is significantly increased in drug-resistant models of hormone-receptor positive disease. The expression of MIR196A also proves to be a robust prognostic factor for patients with advanced and post-menopausal ER+ disease. Conclusion This work sheds light on the normal and abnormal regulation of MIR196A and provides a novel stratification method for therapeutically resistant breast cancer.
Collapse
Affiliation(s)
- Michael J G Milevskiy
- School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, Australia. .,ACRF Stem Cells and Cancer, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
| | - Udai Gujral
- School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, Australia
| | | | - Andrew Stone
- Division of Genomics and Epigenetics, Epigenetics Research Laboratory, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Korinne Northwood
- School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, Australia.,UQ Centre for Clinical Research, The University of Queensland, Herston, QLD, Australia
| | - Lez J Burke
- School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, Australia
| | - Julia M W Gee
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK
| | - Kenneth Nephew
- School of Medicine, Indiana University, Bloomington, IN, USA
| | - Susan Clark
- Division of Genomics and Epigenetics, Epigenetics Research Laboratory, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Melissa A Brown
- School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, Australia
| |
Collapse
|
|
24
|
Tiwari P, Gupta S, Kumar A, Sharma M, Sundararajan VS, Kothari SL, Mathur SK, Medicherla KM, Suravajhala P, Malik B. Characterizing and Functional Assignment of Noncoding RNAs. ENCYCLOPEDIA OF BIOINFORMATICS AND COMPUTATIONAL BIOLOGY 2019:47-59. [DOI: 10.1016/b978-0-12-809633-8.20077-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
25
|
Koh EH, Chernis N, Saha PK, Xiao L, Bader DA, Zhu B, Rajapakshe K, Hamilton MP, Liu X, Perera D, Chen X, York B, Trauner M, Coarfa C, Bajaj M, Moore DD, Deng T, McGuire SE, Hartig SM. miR-30a Remodels Subcutaneous Adipose Tissue Inflammation to Improve Insulin Sensitivity in Obesity. Diabetes 2018; 67:2541-2553. [PMID: 30002134 PMCID: PMC6245225 DOI: 10.2337/db17-1378] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 07/03/2018] [Indexed: 01/08/2023]
Abstract
Chronic inflammation accompanies obesity and limits subcutaneous white adipose tissue (WAT) expandability, accelerating the development of insulin resistance and type 2 diabetes mellitus. MicroRNAs (miRNAs) influence expression of many metabolic genes in fat cells, but physiological roles in WAT remain poorly characterized. Here, we report that expression of the miRNA miR-30a in subcutaneous WAT corresponds with insulin sensitivity in obese mice and humans. To examine the hypothesis that restoration of miR-30a expression in WAT improves insulin sensitivity, we injected adenovirus (Adv) expressing miR-30a into the subcutaneous fat pad of diabetic mice. Exogenous miR-30a expression in the subcutaneous WAT depot of obese mice coupled improved insulin sensitivity and increased energy expenditure with decreased ectopic fat deposition in the liver and reduced WAT inflammation. High-throughput proteomic profiling and RNA-Seq suggested that miR-30a targets the transcription factor STAT1 to limit the actions of the proinflammatory cytokine interferon-γ (IFN-γ) that would otherwise restrict WAT expansion and decrease insulin sensitivity. We further demonstrated that miR-30a opposes the actions of IFN-γ, suggesting an important role for miR-30a in defending adipocytes against proinflammatory cytokines that reduce peripheral insulin sensitivity. Together, our data identify a critical molecular signaling axis, elements of which are involved in uncoupling obesity from metabolic dysfunction.
Collapse
Affiliation(s)
- Eun-Hee Koh
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Natasha Chernis
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Pradip K Saha
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Liuling Xiao
- Center for Bioenergetics, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX
| | - David A Bader
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Bokai Zhu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Kimal Rajapakshe
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX
| | - Mark P Hamilton
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Xia Liu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Dimuthu Perera
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX
| | - Xi Chen
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Brian York
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Cristian Coarfa
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX
| | - Mandeep Bajaj
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX
| | - David D Moore
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Tuo Deng
- Center for Bioenergetics, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital and Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, China
| | - Sean E McGuire
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Sean M Hartig
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX
| |
Collapse
|
|
26
|
MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes. Int J Mol Sci 2018; 19:ijms19123705. [PMID: 30469501 PMCID: PMC6321520 DOI: 10.3390/ijms19123705] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/08/2018] [Accepted: 11/17/2018] [Indexed: 12/21/2022] Open
Abstract
The insulin signaling pathway is composed of a large number of molecules that positively or negatively modulate insulin specific signal transduction following its binding to the cognate receptor. Given the importance of the final effects of insulin signal transduction, it is conceivable that many regulators are needed in order to tightly control the metabolic or proliferative functional outputs. MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively modulate gene expression through their specific binding within the 3′UTR sequence of messenger RNA (mRNA), thus causing mRNA decoy or translational inhibition. In the last decade, miRNAs have been addressed as pivotal cellular rheostats which control many fundamental signaling pathways, including insulin signal transduction. Several studies demonstrated that multiple alterations of miRNAs expression or function are relevant for the development of insulin resistance in type 2 diabetes (T2D); such alterations have been highlighted in multiple insulin target organs including liver, muscles, and adipose tissue. Indirectly, miRNAs have been identified as modulators of inflammation-derived insulin resistance, by controlling/tuning the activity of innate immune cells in insulin target tissues. Here, we review main findings on miRNA functions as modulators of insulin signaling in physiologic- or in T2D insulin resistance- status. Additionally, we report the latest hypotheses of prospective therapies involving miRNAs as potential targets for future drugs in T2D.
Collapse
|
|
27
|
Liu B, Shyr Y, Cai J, Liu Q. Interplay between miRNAs and host genes and their role in cancer. Brief Funct Genomics 2018; 18:255-266. [PMID: 30785618 PMCID: PMC6609535 DOI: 10.1093/bfgp/elz002] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/21/2018] [Accepted: 01/23/2019] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are small endogenous non-coding functional RNAs that post-transcriptionally regulate gene expression. They play essential roles in nearly all biological processes including cell development and differentiation, DNA damage repair, cell death as well as intercellular communication. They are highly involved in cancer, acting as tumor suppressors and/or promoters to modulate cell proliferation, epithelial-mesenchymal transition and tumor invasion and metastasis. Recent studies have shown that more than half of miRNAs are located within protein-coding or non-coding genes. Intragenic miRNAs and their host genes either share the promoter or have independent transcription. Meanwhile, miRNAs work as partners or antagonists of their host genes by fine-tuning their target genes functionally associated with host genes. This review outlined the complicated relationship between intragenic miRNAs and host genes. Focusing on miRNAs known as oncogenes or tumor suppressors in specific cancer types, it studied co-expression relationships between these miRNAs and host genes in the cancer types using TCGA data sets, which validated previous findings and revealed common, tumor-specific and even subtype-specific patterns. These observations will help understand the function of intragenic miRNAs and further develop miRNA therapeutics in cancer.
Collapse
Affiliation(s)
- Baohong Liu
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
| | - Yu Shyr
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jianping Cai
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu Province, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
| | - Qi Liu
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| |
Collapse
|
|
28
|
Splicing factors as regulators of miRNA biogenesis – links to human disease. Semin Cell Dev Biol 2018; 79:113-122. [DOI: 10.1016/j.semcdb.2017.10.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 10/09/2017] [Accepted: 10/09/2017] [Indexed: 12/16/2022]
|
|
29
|
Rodríguez Bautista R, Ortega Gómez A, Hidalgo Miranda A, Zentella Dehesa A, Villarreal-Garza C, Ávila-Moreno F, Arrieta O. Long non-coding RNAs: implications in targeted diagnoses, prognosis, and improved therapeutic strategies in human non- and triple-negative breast cancer. Clin Epigenetics 2018; 10:88. [PMID: 29983835 PMCID: PMC6020372 DOI: 10.1186/s13148-018-0514-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 06/05/2018] [Indexed: 12/31/2022] Open
Abstract
Triple-negative breast cancer (TNBC) has been clinically difficult to manage because of tumor aggressiveness, cellular and histological heterogeneity, and molecular mechanisms’ complexity. All this in turn leads us to evaluate that tumor biological behavior is not yet fully understood. Additionally, the heterogeneity of tumor cells represents a great biomedicine challenge in terms of the complex molecular—genetical-transcriptional and epigenetical—mechanisms, which have not been fully elucidated on human solid tumors. Recently, human breast cancer, but specifically TNBC is under basic and clinical-oncology research in the discovery of new molecular biomarkers and/or therapeutic targets to improve treatment responses, as well as for seeking algorithms for patient stratification, seeking a positive impact in clinical-oncology outcomes and life quality on breast cancer patients. In this sense, important knowledge is emerging regarding several cancer molecular aberrations, including higher genetic mutational rates, LOH, CNV, chromosomal, and epigenetic alterations, as well as transcriptome aberrations in terms of the total gene-coding ribonucleic acids (RNAs), known as mRNAs, as well as non-coding RNA (ncRNA) sequences. In this regard, novel investigation fields have included microRNAs (miRNAs), as well as long ncRNAs (lncRNAs), which have been importantly related and are likely involved in the induction, promotion, progression, and/or clinical therapeutic response trackers of TNBC. Based on this, in general terms according with the five functional archetype classification, the lncRNAs may be involved in the regulation of several molecular mechanisms which include genetic expression, epigenetic, transcriptional, and/or post-transcriptional mechanisms, which are nowadays not totally understood. Here, we have reviewed the main dis-regulated and functionally non- and well-characterized lncRNAs and their likely involvement, from a molecular enrichment and mechanistic point of view, as tumor biomarkers for breast cancer and its specific histological subtype, TNBC. In reference to the abovementioned, it has been described that some lncRNA expression profiles correspond or are associated with the TNBC histological subtype, potentially granting their use for TNBC malignant progression, diagnosis, tumor clinical stage, and likely therapy. Based on this, lncRNAs have been proposed as potential biomarkers which might represent potential predictive tools in the differentiated breast carcinomas versus TNBC malignant disease. Finally, elucidation of the specific or multi-functional archetypal of lncRNAs in breast cancer and TNBC could be fundamental, as these molecular intermediary-regulator “lncRNAs” are widely involved in the genome expression, epigenome regulation, and transcriptional and post-transcriptional tumor biology, which in turn will probably represent a new prospect in clinical and/or therapeutic molecular targets for the oncological management of breast carcinomas in general and also for TNBC patients.
Collapse
Affiliation(s)
- Rubén Rodríguez Bautista
- Thoracic Oncology Unit and Laboratory of Personalized Medicine, Instituto Nacional de Cancerología (INCan), San Fernando #22, Section XVI, Tlalpan, 14080, Mexico City, Mexico.,Biomedical Science Doctorate Program, National Autonomous University of Mexico, Mexico City, Mexico
| | - Alette Ortega Gómez
- Thoracic Oncology Unit and Laboratory of Personalized Medicine, Instituto Nacional de Cancerología (INCan), San Fernando #22, Section XVI, Tlalpan, 14080, Mexico City, Mexico.
| | | | - Alejandro Zentella Dehesa
- Biochemistry Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico D.F, Mexico
| | | | - Federico Ávila-Moreno
- Lung Diseases And Cancer Epigenomics Laboratory, Biomedicine Research Unit (UBIMED), Facultad de Estudios Superiores (FES) Iztacala, National University Autonomous of México (UNAM), Mexico City, Mexico.,Research Unit, National Institute of Respiratory Diseases (INER) "Ismael Cosío Villegas", Mexico City, Mexico
| | - Oscar Arrieta
- Thoracic Oncology Unit and Laboratory of Personalized Medicine, Instituto Nacional de Cancerología (INCan), San Fernando #22, Section XVI, Tlalpan, 14080, Mexico City, Mexico
| |
Collapse
|
|
30
|
Nemlich Y, Baruch EN, Besser MJ, Shoshan E, Bar-Eli M, Anafi L, Barshack I, Schachter J, Ortenberg R, Markel G. ADAR1-mediated regulation of melanoma invasion. Nat Commun 2018; 9:2154. [PMID: 29855470 PMCID: PMC5981216 DOI: 10.1038/s41467-018-04600-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 04/23/2018] [Indexed: 12/13/2022] Open
Abstract
Melanoma cells use different migratory strategies to exit the primary tumor mass and invade surrounding and subsequently distant tissues. We reported previously that ADAR1 expression is downregulated in metastatic melanoma, thereby facilitating proliferation. Here we show that ADAR1 silencing enhances melanoma cell invasiveness and ITGB3 expression. The enhanced invasion is reversed when ITGB3 is blocked with antibodies. Re-expression of wild-type or catalytically inactive ADAR1 establishes this mechanism as independent of RNA editing. We demonstrate that ADAR1 controls ITGB3 expression both at the post-transcriptional and transcriptional levels, via miR-22 and PAX6 transcription factor, respectively. These are proven here as direct regulators of ITGB3 expression. miR-22 expression is controlled by ADAR1 via FOXD1 transcription factor. Clinical relevance is demonstrated in patient-paired progression tissue microarray using immunohistochemistry. The novel ADAR1-dependent and RNA-editing-independent regulation of invasion, mediated by ITGB3, strongly points to a central involvement of ADAR1 in cancer progression and metastasis.
Collapse
Affiliation(s)
- Yael Nemlich
- Ella Lemelbaum Institute for Immuno-Oncology, Ramat-Gan, 52621, Israel
| | - Erez Nissim Baruch
- Ella Lemelbaum Institute for Immuno-Oncology, Ramat-Gan, 52621, Israel.,Sackler Faculty of Medicine, Department of Clinical Microbiology and Immunology, Tel Aviv, 69978, Israel
| | - Michal Judith Besser
- Ella Lemelbaum Institute for Immuno-Oncology, Ramat-Gan, 52621, Israel.,Sackler Faculty of Medicine, Department of Clinical Microbiology and Immunology, Tel Aviv, 69978, Israel
| | - Einav Shoshan
- Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Menashe Bar-Eli
- Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Liat Anafi
- Department of Pathology, Sheba Medical Center, Ramat Gan, 52621, Israel
| | - Iris Barshack
- Department of Pathology, Sheba Medical Center, Ramat Gan, 52621, Israel
| | - Jacob Schachter
- Ella Lemelbaum Institute for Immuno-Oncology, Ramat-Gan, 52621, Israel
| | - Rona Ortenberg
- Ella Lemelbaum Institute for Immuno-Oncology, Ramat-Gan, 52621, Israel
| | - Gal Markel
- Ella Lemelbaum Institute for Immuno-Oncology, Ramat-Gan, 52621, Israel. .,Sackler Faculty of Medicine, Department of Clinical Microbiology and Immunology, Tel Aviv, 69978, Israel. .,Talpiot Medical Leadership Program, Sheba Medical Center, Ramat-Gan, 52621, Israel.
| |
Collapse
|
|
31
|
Galatenko VV, Galatenko AV, Samatov TR, Turchinovich AA, Shkurnikov MY, Makarova JA, Tonevitsky AG. Comprehensive network of miRNA-induced intergenic interactions and a biological role of its core in cancer. Sci Rep 2018; 8:2418. [PMID: 29402894 PMCID: PMC5799291 DOI: 10.1038/s41598-018-20215-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 01/16/2018] [Indexed: 12/22/2022] Open
Abstract
MicroRNAs (miRNAs) are a family of short noncoding RNAs that posttranscriptionally regulate gene expression and play an important role in multiple cellular processes. A significant percentage of miRNAs are intragenic, which is often functionally related to their host genes playing either antagonistic or synergistic roles. In this study, we constructed and analyzed the entire network of intergenic interactions induced by intragenic miRNAs. We further focused on the core of this network, which was defined as a union of nontrivial strongly connected components, i.e., sets of nodes (genes) mutually connected via directed paths. Both the entire network and its core possessed statistically significant non-random properties. Specifically, genes forming the core had high expression levels and low expression variance. Furthermore, the network core did not split into separate components corresponding to individual signalling or metabolic pathways, but integrated genes involved in key cellular processes, including DNA replication, transcription, protein homeostasis and cell metabolism. We suggest that the network core, consisting of genes mutually regulated by their intragenic miRNAs, could coordinate adjacent pathways or homeostatic control circuits, serving as a horizontal inter-circuit link. Notably, expression patterns of these genes had an efficient prognostic potential for breast and colorectal cancer patients.
Collapse
Affiliation(s)
- Vladimir V Galatenko
- Lomonosov Moscow State University, Leninskie Gory 1, 119991, Moscow, Russia. .,SRC Bioclinicum, Ugreshskaya str. 2/85, 115088, Moscow, Russia. .,Tauber Bioinformatics Research Center, University of Haifa, 199 Aba Khoushy Ave., Mount Carmel, 3498838, Haifa, Israel.
| | - Alexey V Galatenko
- Lomonosov Moscow State University, Leninskie Gory 1, 119991, Moscow, Russia
| | - Timur R Samatov
- SRC Bioclinicum, Ugreshskaya str. 2/85, 115088, Moscow, Russia.,Evotec International GmbH, Marie-Curie Str. 7, 37079, Göttingen, Germany
| | | | - Maxim Yu Shkurnikov
- P. Hertsen Moscow Oncology Research Institute, National Center of Medical Radiological Research, Second Botkinsky lane 3, 125284, Moscow, Russia
| | - Julia A Makarova
- P. Hertsen Moscow Oncology Research Institute, National Center of Medical Radiological Research, Second Botkinsky lane 3, 125284, Moscow, Russia.,Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova str. 32, 119991, Moscow, Russia
| | - Alexander G Tonevitsky
- SRC Bioclinicum, Ugreshskaya str. 2/85, 115088, Moscow, Russia. .,P. Hertsen Moscow Oncology Research Institute, National Center of Medical Radiological Research, Second Botkinsky lane 3, 125284, Moscow, Russia.
| |
Collapse
|
|
32
|
Shi H, Fu Q, Li S, Hu X, Tian R, Yao G, Zhao H, Wang J. Bta-miR-2411 attenuates bovine viral diarrhea virus replication via directly suppressing Pelota protein in Madin-Darby bovine kidney cells. Vet Microbiol 2018; 215:43-48. [DOI: 10.1016/j.vetmic.2018.01.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Revised: 01/06/2018] [Accepted: 01/08/2018] [Indexed: 01/11/2023]
|
|
33
|
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that can regulate gene expression playing vital role in nearly all biological pathways. Even though miRNAs have been intensely studied for more than two decades, information regarding miRNA transcription regulation remains limited. The rapid cleavage of primary miRNA transcripts (pri-miRNAs) by Drosha in the nucleus hinders their identification with conventional RNA-seq approaches. Identifying the transcription start site (TSS) of miRNAs will enable genome-wide identification of their expression regulators, including transcription factors (TFs), other non-coding RNAs (ncRNAs) and epigenetic modifiers, providing significant breakthroughs in understanding the mechanisms underlying miRNA expression in development and disease. Here we present a protocol that utilizes microTSS, a versatile computational framework for accurate and single-nucleotide resolution miRNA TSS predictions as well as miRGen, a database of miRNA gene TSSs coupled with genome-wide maps of TF binding sites.
Collapse
Affiliation(s)
- Georgios Georgakilas
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA
- Epigenetics Institute at Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Nikos Perdikopanis
- DIANA-Lab, Hellenic Pasteur Institute, Athens, Greece
- Department of Electrical and Computer Engineering, University of Thessaly, Volos, Greece
| | - Artemis G Hatzigeorgiou
- DIANA-Lab, Hellenic Pasteur Institute, Athens, Greece.
- Department of Electrical and Computer Engineering, University of Thessaly, Volos, Greece.
| |
Collapse
|
|
34
|
|
|
35
|
Chen J, Zhu D, Sun Y. Cap-seq reveals complicated miRNA transcriptional mechanisms in C. elegans and mouse. QUANTITATIVE BIOLOGY 2017. [DOI: 10.1007/s40484-017-0123-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
|
|
36
|
Sun Y, Ji F, Kumar MR, Zheng X, Xiao Y, Liu N, Shi J, Wong L, Forgues M, Qin LX, Tang ZY, Zhao X, Wang XW, Ji J. Transcriptome integration analysis in hepatocellular carcinoma reveals discordant intronic miRNA-host gene pairs in expression. Int J Biol Sci 2017; 13:1438-1449. [PMID: 29209147 PMCID: PMC5715526 DOI: 10.7150/ijbs.20836] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 09/21/2017] [Indexed: 12/13/2022] Open
Abstract
Intronic miRNAs, residing in intronic regions of host genes, are thought to be co-transcribed from their host genes and present consistent expression patterns with host genes. Recent studies reported a few intronic miRNAs with discordant expression with their host genes. We therefore aimed to understand the expression pattern of intronic miRNAs and their host genes in hepatocellular carcinoma (HCC) and reveal possible associated molecular mechanisms. Our genome wide integration analysis of miRNA and mRNA transcriptomes, in three dataset from 550 patients with HCC, found that a large amount of miRNA-host gene pairs were discordantly expressed. Consistent results were also revealed in 775 breast cancer patients. Further, most of HCC-related intronic miRNAs were predicted to have distinct upstream regulators and independent proximal promoter signals from host genes. The discordant expression of representative pairs, miR-26s/CTDSPs, was validated experimentally. We have also identified the independent transcriptional start site, promoter signal, and transcriptional factor of miR-26b from its host gene. Collectively, discordant expression of intronic miRNAs and their host genes was relatively ubiquitous and the intronic miRNA “independent transcription” may partially contribute to such a phenotype.
Collapse
Affiliation(s)
- Yulin Sun
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China.,University of Hawai'i Cancer Center, Honolulu, HI, 96813, USA.,State Key Laboratory of Molecular Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fubo Ji
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Mia R Kumar
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Xin Zheng
- Sinowell Beijing Tech Ltd, Beijing, 100045, China
| | - Yi Xiao
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Niya Liu
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Jiong Shi
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, 20892, USA.,Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China, 200433
| | - Linda Wong
- University of Hawai'i Cancer Center, Honolulu, HI, 96813, USA.,Department of Surgery, John A. Burns School of Medicine, University of Hawai'i, Honolulu, HI, 96813, USA
| | - Marshonna Forgues
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Lun-Xiu Qin
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China, 200433
| | - Zhao-You Tang
- Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China, 200433
| | - Xiaohang Zhao
- State Key Laboratory of Molecular Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xin Wei Wang
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Junfang Ji
- Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| |
Collapse
|
|
37
|
Liu Q, Wang J, Zhao Y, Li CI, Stengel KR, Acharya P, Johnston G, Hiebert SW, Shyr Y. Identification of active miRNA promoters from nuclear run-on RNA sequencing. Nucleic Acids Res 2017; 45:e121. [PMID: 28460090 PMCID: PMC5737662 DOI: 10.1093/nar/gkx318] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 04/13/2017] [Indexed: 12/27/2022] Open
Abstract
The genome-wide identification of microRNA transcription start sites (miRNA TSSs) is essential for understanding how miRNAs are regulated in development and disease. In this study, we developed mirSTP (mirna transcription Start sites Tracking Program), a probabilistic model for identifying active miRNA TSSs from nascent transcriptomes generated by global run-on sequencing (GRO-seq) and precision run-on sequencing (PRO-seq). MirSTP takes advantage of characteristic bidirectional transcription signatures at active TSSs in GRO/PRO-seq data, and provides accurate TSS prediction for human intergenic miRNAs at a high resolution. MirSTP performed better than existing generalized and experiment specific methods, in terms of the enrichment of various promoter-associated marks. MirSTP analysis of 27 human cell lines in 183 GRO-seq and 28 PRO-seq experiments identified TSSs for 480 intergenic miRNAs, indicating a wide usage of alternative TSSs. By integrating predicted miRNA TSSs with matched ENCODE transcription factor (TF) ChIP-seq data, we connected miRNAs into the transcriptional circuitry, which provides a valuable source for understanding the complex interplay between TF and miRNA. With mirSTP, we not only predicted TSSs for 72 miRNAs, but also identified 12 primary miRNAs with significant RNA polymerase pausing alterations after JQ1 treatment; each miRNA was further validated through BRD4 binding to its predicted promoter. MirSTP is available at http://bioinfo.vanderbilt.edu/mirSTP/.
Collapse
Affiliation(s)
- Qi Liu
- Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.,Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Jing Wang
- Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.,Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Yue Zhao
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Chung-I Li
- Department of Statistics, National Cheng Kung University, Tainan 70101, Taiwan
| | - Kristy R Stengel
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Pankaj Acharya
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Gretchen Johnston
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Scott W Hiebert
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.,Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Yu Shyr
- Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.,Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.,Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.,Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| |
Collapse
|
|
38
|
Hathaway QA, Pinti MV, Durr AJ, Waris S, Shepherd DL, Hollander JM. Regulating microRNA expression: at the heart of diabetes mellitus and the mitochondrion. Am J Physiol Heart Circ Physiol 2017; 314:H293-H310. [PMID: 28986361 DOI: 10.1152/ajpheart.00520.2017] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes mellitus is a major risk factor for cardiovascular disease and mortality. Uncontrolled type 2 diabetes mellitus results in a systemic milieu of increased circulating glucose and fatty acids. The development of insulin resistance in cardiac tissue decreases cellular glucose import and enhances mitochondrial fatty acid uptake. While triacylglycerol and cytotoxic lipid species begin to accumulate in the cardiomyocyte, the energy substrate utilization ratio of free fatty acids to glucose changes to almost entirely free fatty acids. Accumulating evidence suggests a role of miRNA in mediating this metabolic transition. Energy substrate metabolism, apoptosis, and the production and response to excess reactive oxygen species are regulated by miRNA expression. The current momentum for understanding the dynamics of miRNA expression is limited by a lack of understanding of how miRNA expression is controlled. While miRNAs are important regulators in both normal and pathological states, an additional layer of complexity is added when regulation of miRNA regulators is considered. miRNA expression is known to be regulated through a number of mechanisms, which include, but are not limited to, epigenetics, exosomal transport, processing, and posttranscriptional sequestration. The purpose of this review is to outline how mitochondrial processes are regulated by miRNAs in the diabetic heart. Furthermore, we will highlight the regulatory mechanisms, such as epigenetics, exosomal transport, miRNA processing, and posttranslational sequestration, that participate as regulators of miRNA expression. Additionally, current and future treatment strategies targeting dysfunctional mitochondrial processes in the diseased myocardium, as well as emerging miRNA-based therapies, will be summarized.
Collapse
Affiliation(s)
- Quincy A Hathaway
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia.,Mitochondria, Metabolism, and Bioenergetics Working Group, West Virginia University School of Medicine , Morgantown, West Virginia.,Toxicology Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
| | - Mark V Pinti
- Division of Pharmaceutical and Pharmacological Sciences, West Virginia School of Pharmacy , Morgantown, West Virginia
| | - Andrya J Durr
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia.,Mitochondria, Metabolism, and Bioenergetics Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
| | - Shanawar Waris
- Department of Biomedical Engineering, West Virginia College of Engineering , Morgantown, West Virginia
| | - Danielle L Shepherd
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia
| | - John M Hollander
- Division of Exercise Physiology, West Virginia University School of Medicine , Morgantown, West Virginia.,Mitochondria, Metabolism, and Bioenergetics Working Group, West Virginia University School of Medicine , Morgantown, West Virginia.,Toxicology Working Group, West Virginia University School of Medicine , Morgantown, West Virginia
| |
Collapse
|
|
39
|
Saraiva C, Esteves M, Bernardino L. MicroRNA: Basic concepts and implications for regeneration and repair of neurodegenerative diseases. Biochem Pharmacol 2017; 141:118-131. [DOI: 10.1016/j.bcp.2017.07.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 07/07/2017] [Indexed: 12/25/2022]
|
|
40
|
Ma X, Qi S, Duan Z, Liao H, Yang B, Wang W, Tan J, Li Q, Xia X. Long non-coding RNA LOC554202 modulates chordoma cell proliferation and invasion by recruiting EZH2 and regulating miR-31 expression. Cell Prolif 2017; 50. [PMID: 28963737 DOI: 10.1111/cpr.12388] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Accepted: 08/28/2017] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Chordoma is a rare malignant bone tumour arising from notochordal remnants. Long non-coding RNA LOC554202, as the host gene of miR-31, contributes to various cancer developments. However, little is known about the biological function of LOC554202 in chordoma. Here, the relationship between LncRNA LOC554202, miR-31 and EZH2 was elucidated in chordoma. MATERIALS AND METHODS The levels of LOC554402, miR-31, EZH2, RNF144B, and epithelial-mesenchymal transition (EMT) markers were measured in chordoma tissues and the chordoma cell lines via quantitative real-time PCR (qRT-PCR) or Western blot. FISH assay demonstrated the LOC554402 expression in chordoma tissues. The chordoma cell lines, U-CH1 and JHC7, were transfected with siRNA or miRNA mimics and analysed for cell proliferation ability, apoptosis, cell migration, and invasion. RNA pull down, RIP assay, and Luciferase Reporter Assay were used to analyze the interaction between LOC554202 and EZH2. Animal tumour xenografts were generated, and qRT-PCR was performed to investigate EZH2, miR-31, and RNB144B expression on tumour growth in vivo. RESULTS We found elevated expression of LOC554202 was associated with a decreased level of miR-31 in cancer tissues. Knockdown of LOC554202 or overexpression of miR-31 suppressed the proliferation, migration, and invasion of chordoma cells. Unexpectedly, EZH2 as a binding protein of LOC554202, and it was positively regulated by LOC554202, leading to the reduced expression of miR-31. Furthermore, the impaired function of miR-31 restored expression of the oncogene RNF144B and maintained the metastasis-promoting activity in vitro. The results in vivo confirmed the anti-tumour effects of knockdown of LOC554202, which inhibited EZH2/miR-31 to activate the oncogene RNF144B. CONCLUSION Our results suggest that LOC554202 may play an important role in the progression of chordoma by the direct upregulation of EZH2 and indirect promotion of RNF144B via miR-31.
Collapse
Affiliation(s)
- Xianli Ma
- College of Pharmacy, Guilin Medical University, Guilin, Guangxi, China
| | - Shengjin Qi
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Zhenying Duan
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Hongzhan Liao
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Baohua Yang
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Wenbo Wang
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Jie Tan
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin, Guangxi, China
| | - Qinghua Li
- Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin, Guangxi, China
| | - Xuewei Xia
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| |
Collapse
|
|
41
|
Yeung CLA, Tsang TY, Yau PL, Kwok TT. Human papillomavirus type 16 E6 suppresses microRNA-23b expression in human cervical cancer cells through DNA methylation of the host gene C9orf3. Oncotarget 2017; 8:12158-12173. [PMID: 28077801 PMCID: PMC5355333 DOI: 10.18632/oncotarget.14555] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 11/21/2016] [Indexed: 11/25/2022] Open
Abstract
Oncogenic protein E6 of human papillomavirus type 16 (HPV-16) is believed to involve in the aberrant methylation in cervical cancer as it upregulates DNA methyltransferase 1 (DNMT1) through tumor suppressor p53. In addition, DNA demethylating agent induces the expression of one of the HPV-16 E6 regulated microRNAs (miRs), miR-23b, in human cervical carcinoma SiHa cells. Thus, the importance of DNA methylation and miR-23b in HPV-16 E6 associated cervical cancer development is investigated. In the present study, however, it is found that miR-23b is not embedded in any typical CpG island. Nevertheless, a functional CpG island is predicted in the promoter region of C9orf3, the host gene of miR-23b, and is validated by methylation-specific PCR and bisulfite genomic sequencing analyses. Besides, c-MET is confirmed to be a target gene of miR-23b. Silencing of HPV-16 E6 is found to increase the expression of miR-23b, decrease the expression of c-MET and thus induce the apoptosis of SiHa cells through the c-MET downstream signaling pathway. Taken together, the tumor suppressive miR-23b is epigenetically inactivated through its host gene C9orf3 and this is probably a critical pathway during HPV-16 E6 associated cervical cancer development.
Collapse
Affiliation(s)
- Chi Lam Au Yeung
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.,Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tsun Yee Tsang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Pak Lun Yau
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Tim Tak Kwok
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| |
Collapse
|
|
42
|
Hasegawa T, Adachi R, Iwakata H, Takeno T, Sato K, Sakamaki T. ErbB2 signaling epigenetically suppresses microRNA-205 transcription via Ras/Raf/MEK/ERK pathway in breast cancer. FEBS Open Bio 2017; 7:1154-1165. [PMID: 28781955 PMCID: PMC5537069 DOI: 10.1002/2211-5463.12256] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 05/05/2017] [Accepted: 05/25/2017] [Indexed: 01/28/2023] Open
Abstract
We previously reported that microRNA-205 (miR-205) is downregulated by overexpression of the receptor tyrosine kinase ErbB2 and that ectopic transfection of miR-205 precursor decreases ErbB2 tumorigenicity in soft agar. In this study, we further analyzed the regulatory mechanisms linking ErbB2 overexpression and miR-205 downregulation. In ErbB2-overexpressing breast epithelial cells, miR-205 expression was significantly increased by treatment with MEK inhibitor U0126 or PD98059, Raf-1 inhibitor ZM-336372, and ERK inhibitor SCH772984, but PI3K inhibitor LY294002 and p38 MAPK inhibitor SB203580 had no effect. We established breast epithelial cells overexpressing RafCAAX, a constitutively active form of Raf-1, and showed that overexpression of RafCAAX dramatically reduced miR-205 expression. In RafCAAX-overexpressing cells, miR-205 expression was also significantly increased by SCH772984. Moreover, miR-205 expression was significantly increased by treatment with DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine and expression of several DNMT family members was increased in both ErbB2- and RafCAAX-overexpressing cells. DNA methylation analysis by bisulfite sequencing revealed that the putative miR-205 promoters were predominantly hypermethylated in both ErbB2- and RafCAAX-overexpressing cells. Reporter activity of the putative miR-205 promoters was reduced in both ErbB2-overexpressing and RafCAAX-overexpressing cells. Together, these findings indicate that ErbB2 signaling epigenetically suppresses miR-205 transcription via the Ras/Raf/MEK/ERK pathway.
Collapse
Affiliation(s)
- Takuya Hasegawa
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Ryohei Adachi
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Hitoshi Iwakata
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Takayoshi Takeno
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Koji Sato
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| | - Toshiyuki Sakamaki
- Department of Public Health Faculty of Pharmaceutical Sciences Niigata University of Pharmacy and Applied Life Sciences Japan
| |
Collapse
|
|
43
|
Wang H, Luo J, He Q, Yao D, Wu J, Loor JJ. miR-26b promoter analysis reveals regulatory mechanisms by lipid-related transcription factors in goat mammary epithelial cells. J Dairy Sci 2017; 100:5837-5849. [DOI: 10.3168/jds.2016-12440] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 03/29/2017] [Indexed: 11/19/2022]
|
|
44
|
Kulkarni V, Uttamani JR, Naqvi AR, Nares S. microRNAs: Emerging players in oral cancers and inflammatory disorders. Tumour Biol 2017; 39:1010428317698379. [PMID: 28459366 DOI: 10.1177/1010428317698379] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Association of oral diseases and disorders with altered microRNA profiles is firmly recognized. These evidences support the potential use of microRNAs as therapeutic tools for diagnosis, prognosis, and treatment of various diseases. In this review, we highlight the association of altered microRNA signatures in oral cancers and oral inflammatory diseases. Advances in our ability to detect microRNAs in human sera and saliva further highlight their clinical value as potential biomarkers. We have discussed key mechanisms underlying microRNA dysregulation in pathological conditions. The use of microRNAs in diagnostics and their potential therapeutic value in the treatment of oral diseases are reviewed.
Collapse
Affiliation(s)
- Varun Kulkarni
- 1 Department of Periodontics, College of Dentistry, The University of Illinois at Chicago, Chicago, IL, USA
| | - Juhi Raju Uttamani
- 1 Department of Periodontics, College of Dentistry, The University of Illinois at Chicago, Chicago, IL, USA
| | - Afsar Raza Naqvi
- 1 Department of Periodontics, College of Dentistry, The University of Illinois at Chicago, Chicago, IL, USA
| | - Salvador Nares
- 1 Department of Periodontics, College of Dentistry, The University of Illinois at Chicago, Chicago, IL, USA
| |
Collapse
|
|
45
|
Methods of MicroRNA Promoter Prediction and Transcription Factor Mediated Regulatory Network. BIOMED RESEARCH INTERNATIONAL 2017; 2017:7049406. [PMID: 28656148 PMCID: PMC5474535 DOI: 10.1155/2017/7049406] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 05/07/2017] [Indexed: 11/17/2022]
Abstract
MicroRNAs (miRNAs) are short (~22 nucleotides) noncoding RNAs and disseminated throughout the genome, either in the intergenic regions or in the intronic sequences of protein-coding genes. MiRNAs have been proved to play important roles in regulating gene expression. Hence, understanding the transcriptional mechanism of miRNA genes is a very critical step to uncover the whole regulatory network. A number of miRNA promoter prediction models have been proposed in the past decade. This review summarized several most popular miRNA promoter prediction models which used genome sequence features, or other features, for example, histone markers, RNA Pol II binding sites, and nucleosome-free regions, achieved by high-throughput sequencing data. Some databases were described as resources for miRNA promoter information. We then performed comprehensive discussion on prediction and identification of transcription factor mediated microRNA regulatory networks.
Collapse
|
|
46
|
Guo W, Dong Z, Liu S, Qiao Y, Kuang G, Guo Y, Shen S, Liang J. Promoter hypermethylation-mediated downregulation of miR-770 and its host gene MEG3, a long non-coding RNA, in the development of gastric cardia adenocarcinoma. Mol Carcinog 2017; 56:1924-1934. [PMID: 28345805 DOI: 10.1002/mc.22650] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 03/23/2017] [Indexed: 12/24/2022]
Abstract
Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 which encodes an lncRNA and is downregulated in an expanding list of cancer cell lines and primary human cancers. The miR-770 is transcribed from the intronic sequence of MEG3 and MEG3 may be the host gene for miR-770. However, the biological role of MEG3 and miR-770 in gastric cardia adenocarcinoma (GCA) development and prognosis is poorly defined. The present study was to investigate the function and methylation status of MEG3 in GCA, and further to detect the functional association of miR-770 and its host gene MEG3 in GCA carcinogenesis and prognosis. MEG3 and miR-770 was significantly downregulated in GCA patients and cell lines, and their expression was associated with TNM stage and lymph node metastasis. Overexpression of MEG3 and miR-770 inhibited gastric cancer cell proliferation and invasion in vitro. Furthermore, the expression level of MEG3 and miR-770 was significantly increased in cancer cells after treated with 5-Aza-dC. The aberrant hypermethylation of proximal promoter and enhancer region of MEG3 was detected in GCA tissues. In addition, the proximal promoter and enhancer region hypermethylation and dysregulation of MEG3 and miR-770 were associated with poorer GCA patients' survival. These findings suggest that miR-770 and its host gene MEG3 may play tumor suppressor role and hypermethylation of proximal promoter and enhancer region may be one of the critical mechanisms in inactivation of MEG3 and miR-770 in GCA development. MEG3 and miR-770 may be used as potential biomarkers in predicting GCA patients' prognosis.
Collapse
Affiliation(s)
- Wei Guo
- Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhiming Dong
- Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Shengnan Liu
- Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yiling Qiao
- Special Care Hospital of Hebei Province, Shijiazhuang, Hebei, China
| | - Gang Kuang
- Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yanli Guo
- Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Supeng Shen
- Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jia Liang
- Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| |
Collapse
|
|
47
|
Bhattacharya M, Sharma AR, Sharma G, Patra BC, Nam JS, Chakraborty C, Lee SS. The crucial role and regulations of miRNAs in zebrafish development. PROTOPLASMA 2017; 254:17-31. [PMID: 26820151 DOI: 10.1007/s00709-015-0931-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 12/10/2015] [Indexed: 06/05/2023]
Abstract
To comprehend the events during developmental biology, fundamental knowledge about the basic machinery of regulation is a prerequisite. MicroRNA (miRNAs) act as regulators in most of the biological processes and recently, it has been concluded that miRNAs can act as modulatory factors even during developmental process from lower to higher animal. Zebrafish, because of its favorable attributes like tiny size, transparent embryo, and rapid external embryonic development, has gained a preferable status among all other available experimental animal models. Currently, zebrafish is being utilized for experimental studies related to stem cells, regenerative molecular medicine as well drug discovery. Therefore, it is important to understand precisely about the various miRNAs that controls developmental biology of this vertebrate model. In here, we have discussed about the miRNA-controlled zebrafish developmental stages with a special emphasis on different miRNA families such as miR-430, miR-200, and miR-133. Moreover, we have also reviewed the role of various miRNAs during embryonic and vascular development stages of zebrafish. In addition, efforts have been made to summarize the involvement of miRNAs in the development of different body parts such as the brain, eye, heart, muscle, and fin, etc. In each section, we have tried to fulfill the gaps of zebrafish developmental biology with the help of available knowledge of miRNA research. We hope that precise knowledge about the miRNA-regulated developmental stages of zebrafish may further help the researchers to efficiently utilize this vertebrate model for experimental purpose.
Collapse
Affiliation(s)
- Manojit Bhattacharya
- Aquaculture Research Unit, Department of Zoology, Vidyasagar University, Midnapore, 721102, West Bengal, India
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 200704, South Korea
| | - Ashish Ranjan Sharma
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 200704, South Korea
| | - Garima Sharma
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 200704, South Korea
- Amity Institute of Nanotechnology, Amity University Uttar Pradesh, Noida, 201313, India
| | - Bidhan Chandra Patra
- Aquaculture Research Unit, Department of Zoology, Vidyasagar University, Midnapore, 721102, West Bengal, India
| | - Ju-Suk Nam
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 200704, South Korea
| | - Chiranjib Chakraborty
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 200704, South Korea.
- Department of Bio-informatics, School of Computer and Information Sciences, Galgotias University, Greater Noida, 201306, India.
| | - Sang-Soo Lee
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, 200704, South Korea.
- Department of Orthopedic Surgery, Hallym University Hospital-College of Medicine, Chuncheon-si, Gangwon-do, 200-704, Republic of Korea.
| |
Collapse
|
|
48
|
Chen J, Zhu J. Elevated Expression Levels of Long Non-Coding RNA, Loc554202, Are Predictive of Poor Prognosis in Cervical Cancer. TOHOKU J EXP MED 2017; 243:165-172. [DOI: 10.1620/tjem.243.165] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Jiewen Chen
- Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiaotong University and Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics
| | - Jie Zhu
- Department of Obstetrics & Gynecology, Shanghai Jiaotong University Affiliated Renji Hospital
| |
Collapse
|
|
49
|
Han C, Shen JK, Hornicek FJ, Kan Q, Duan Z. Regulation of microRNA-1 (miR-1) expression in human cancer. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2016; 1860:227-232. [PMID: 27923712 DOI: 10.1016/j.bbagrm.2016.12.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Revised: 11/30/2016] [Accepted: 12/02/2016] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRs) have been found to play important roles in tumorigenesis, apoptosis, metastasis, and drug resistance in cancer. Among a number of miRs, miR-1 was shown to be predominantly downregulated in almost all examined human cancers. As a tumor suppressor miR involved in post-transcriptional regulation of crucial tumor associated gene expression, miR-1 represents a promising target for anticancer therapy. Re-expression of miR-1 can suppress cancer cell proliferation, promote apoptosis, and reverse drug resistance in cancers both in vitro and in vivo. Recently, the regulatory mechanisms of miR-1 expression have been studied in various cancers in different model systems. In this review, we summarize the mechanisms of miR-1 expression through epigenetic, transcriptional, and post-transcriptional regulation. These regulatory mechanisms of miR-1 expression could help us to understand the functions of altered miR-1 expression and provide valuable insights for further investigations into miR-1 based cancer therapy.
Collapse
Affiliation(s)
- Chao Han
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Jacson K Shen
- Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Francis J Hornicek
- Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Quancheng Kan
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.
| | - Zhenfeng Duan
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, USA.
| |
Collapse
|
|
50
|
Jeong G, Lim YH, Kim YK. Precise mapping of the transcription start sites of human microRNAs using DROSHA knockout cells. BMC Genomics 2016; 17:908. [PMID: 27835943 PMCID: PMC5106785 DOI: 10.1186/s12864-016-3252-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Accepted: 11/04/2016] [Indexed: 12/31/2022] Open
Abstract
Background The expression of microRNAs (miRNAs) is primarily regulated during their transcription. However, the transcriptional regulation of miRNA genes has not been studied extensively owing to the lack of sufficient information about the promoters and transcription start sites of most miRNAs. Results In this study, we identified the transcription start sites of human primary miRNAs (pri-miRNAs) using DROSHA knockout cells. DROSHA knockout resulted in increased accumulation of pri-miRNAs and facilitated the precise mapping of their 5′ end nucleotides using the rapid amplification of cDNA ends (RACE) technique. By analyzing the promoter region encompassing the transcription start sites of miRNAs, we found that the unrelated miRNAs in their sequences have many common elements in their promoters for binding the same transcription factors. Moreover, by analyzing intronic miRNAs, we also obtained comprehensive evidence that miRNA-harboring introns are spliced more slowly than other introns. Conclusions The precisely mapped transcription start sites of pri-miRNAs, and the list of transcription factors for pri-miRNAs regulation, will be valuable resources for future studies to understand the regulatory network of miRNAs. Electronic supplementary material The online version of this article (doi:10.1186/s12864-016-3252-7) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Geon Jeong
- Department of Biochemistry, Chonnam National University Medical School, Gwangju, Korea.,Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju, Korea
| | - Yeong-Hwan Lim
- Department of Biochemistry, Chonnam National University Medical School, Gwangju, Korea.,Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju, Korea
| | - Young-Kook Kim
- Department of Biochemistry, Chonnam National University Medical School, Gwangju, Korea. .,Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju, Korea.
| |
Collapse
|