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      MiR-15b and miR-322 inhibit SETD3 expression to repress muscle cell differentiation

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          Abstract

          SETD3 is a member of SET-domain containing methyltransferase family, which plays critical roles in various biological events. It has been shown that SETD3 could regulate the transcription of myogenic regulatory genes in C2C12 differentiation and promote myoblast determination. However, how SETD3 is regulated during myoblast differentiation is still unknown. Here, we report that two important microRNAs (miRNAs) could repress SETD3 and negatively contribute to myoblast differentiation. Using microRNA (miRNA) prediction engines, we identify and characterize miR-15b and miR-322 as the primary miRNAs that repress the expression of SETD3 through directly targeting the 3’-untranslated region of SETD3 gene. Functionally, overexpression of miR-15b or miR-322 leads to the repression of endogenous SETD3 expression and the inhibition of myoblast differentiation, whereas inhibition of miR-15b or miR-322 derepresses endogenous SETD3 expression and facilitates myoblast differentiation. In addition, knockdown SETD3 in miR-15b or miR-322 repressed myoblasts is able to rescue the facilitated differentiation phenotype. More interestingly, we revealed that transcription factor E2F1 or FAM3B positively or negatively regulates miR-15b or miR-322 expression, respectively, during muscle cell differentiation, which in turn affects SETD3 expression. Therefore, our results establish two parallel cascade regulatory pathways, in which transcription factors regulate microRNAs fates, thereby controlling SETD3 expression and eventually determining skeletal muscle differentiation.

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          Most cited references32

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          Muscle-specific microRNA miR-206 promotes muscle differentiation

          Three muscle-specific microRNAs, miR-206, -1, and -133, are induced during differentiation of C2C12 myoblasts in vitro. Transfection of miR-206 promotes differentiation despite the presence of serum, whereas inhibition of the microRNA by antisense oligonucleotide inhibits cell cycle withdrawal and differentiation, which are normally induced by serum deprivation. Among the many mRNAs that are down-regulated by miR-206, the p180 subunit of DNA polymerase α and three other genes are shown to be direct targets. Down-regulation of the polymerase inhibits DNA synthesis, an important component of the differentiation program. The direct targets are decreased by mRNA cleavage that is dependent on predicted microRNA target sites. Unlike small interfering RNA–directed cleavage, however, the 5′ ends of the cleavage fragments are distributed and not confined to the target sites, suggesting involvement of exonucleases in the degradation process. In addition, inhibitors of myogenic transcription factors, Id1-3 and MyoR, are decreased upon miR-206 introduction, suggesting the presence of additional mechanisms by which microRNAs enforce the differentiation program.
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            Gene regulatory networks and transcriptional mechanisms that control myogenesis.

            We discuss the upstream regulators of myogenesis that lead to the activation of myogenic determination genes and subsequent differentiation, focusing on the mouse model. Key upstream genes, such as Pax3 and Pax7, Six1 and Six4, or Pitx2, participate in gene regulatory networks at different sites of skeletal muscle formation. MicroRNAs also intervene, with emerging evidence for the role of other noncoding RNAs. Myogenic determination and subsequent differentiation depend on members of the MyoD family. We discuss new insights into mechanisms underlying the transcriptional activity of these factors. Copyright © 2014 Elsevier Inc. All rights reserved.
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              MyoD and the transcriptional control of myogenesis.

              The basic helix-loop-helix myogenic regulatory factors MyoD, Myf5, myogenin and MRF4 have critical roles in skeletal muscle development. Together with the Mef2 proteins and E proteins, these transcription factors are responsible for coordinating muscle-specific gene expression in the developing embryo. This review highlights recent studies regarding the molecular mechanisms by which the muscle-specific myogenic bHLH proteins interact with other regulatory factors to coordinate gene expression in a controlled and ordered manner.
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                Author and article information

                Contributors
                +86-27-68752401 , hainingdu@whu.edu.cn
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                22 February 2019
                22 February 2019
                March 2019
                : 10
                : 3
                : 183
                Affiliations
                [1 ]ISNI 0000 0001 2331 6153, GRID grid.49470.3e, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, , Wuhan University, ; 430072 Wuhan, China
                [2 ]Hubei Key Laboratory of Medical Information Analysis & Tumor Diagnosis and Treatment, 430074 Wuhan, China
                [3 ]ISNI 0000 0001 2331 6153, GRID grid.49470.3e, Medical Research Institute, School of Medicine, , Wuhan University, ; 430071 Wuhan, China
                Author information
                http://orcid.org/0000-0001-8062-5411
                Article
                1432
                10.1038/s41419-019-1432-5
                6385263
                30796205
                fa581713-be3d-4585-aa6c-7b9271360508
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 26 December 2018
                : 1 February 2019
                : 7 February 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 31770843, 31271369
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100007046, Wuhan University (WHU);
                Award ID: 2042018kf0217
                Award ID: 2042018kf0217
                Award Recipient :
                Funded by: the Major State Basic Research Development Program of China (2013CB910700)
                Categories
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                © The Author(s) 2019

                Cell biology
                Cell biology

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