BRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis

Abstract Myogenic differentiation proceeds through a highly coordinated cascade of gene activation that necessitates epigenomic changes in chromatin structure. Using a screen of small molecule epigenetic probes we identified three compounds which inhibited myogenic differentiation in C2C12 myoblasts...

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Autores principales:	Thomas C. Roberts, Usue Etxaniz, Alessandra Dall’Agnese, Shwu-Yuan Wu, Cheng-Ming Chiang, Paul E. Brennan, Matthew J. A. Wood, Pier Lorenzo Puri
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d950695199844891be7ec67ea14b2596
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spelling	oai:doaj.org-article:d950695199844891be7ec67ea14b25962021-12-02T11:52:20ZBRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis10.1038/s41598-017-06483-72045-2322https://doaj.org/article/d950695199844891be7ec67ea14b25962017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06483-7https://doaj.org/toc/2045-2322Abstract Myogenic differentiation proceeds through a highly coordinated cascade of gene activation that necessitates epigenomic changes in chromatin structure. Using a screen of small molecule epigenetic probes we identified three compounds which inhibited myogenic differentiation in C2C12 myoblasts; (+)-JQ1, PFI-1, and Bromosporine. These molecules target Bromodomain and Extra Terminal domain (BET) proteins, which are epigenetic readers of acetylated histone lysine tail residues. BETi-mediated anti-myogenic effects were also observed in a model of MYOD1-mediated myogenic conversion of human fibroblasts, and in primary mouse and human myoblasts. All three BET proteins BRD2, BRD3 and BRD4 exhibited distinct and dynamic patterns of protein expression over the course of differentiation without concomitant changes in mRNA levels, suggesting that BET proteins are regulated at the post-transcriptional level. Specific BET protein knockdown by RNA interference revealed that BRD4 was required for myogenic differentiation, whereas BRD3 down-regulation resulted in enhanced myogenic differentiation. ChIP experiments revealed a preferential binding of BRD4 to the Myog promoter during C2C12 myoblast differentiation, co-incident with increased levels of H3K27 acetylation. These results have identified an essential role for BET proteins in the regulation of skeletal myogenesis, and assign distinct functions to BRD3 and BRD4.Thomas C. RobertsUsue EtxanizAlessandra Dall’AgneseShwu-Yuan WuCheng-Ming ChiangPaul E. BrennanMatthew J. A. WoodPier Lorenzo PuriNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thomas C. Roberts Usue Etxaniz Alessandra Dall’Agnese Shwu-Yuan Wu Cheng-Ming Chiang Paul E. Brennan Matthew J. A. Wood Pier Lorenzo Puri BRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis
description	Abstract Myogenic differentiation proceeds through a highly coordinated cascade of gene activation that necessitates epigenomic changes in chromatin structure. Using a screen of small molecule epigenetic probes we identified three compounds which inhibited myogenic differentiation in C2C12 myoblasts; (+)-JQ1, PFI-1, and Bromosporine. These molecules target Bromodomain and Extra Terminal domain (BET) proteins, which are epigenetic readers of acetylated histone lysine tail residues. BETi-mediated anti-myogenic effects were also observed in a model of MYOD1-mediated myogenic conversion of human fibroblasts, and in primary mouse and human myoblasts. All three BET proteins BRD2, BRD3 and BRD4 exhibited distinct and dynamic patterns of protein expression over the course of differentiation without concomitant changes in mRNA levels, suggesting that BET proteins are regulated at the post-transcriptional level. Specific BET protein knockdown by RNA interference revealed that BRD4 was required for myogenic differentiation, whereas BRD3 down-regulation resulted in enhanced myogenic differentiation. ChIP experiments revealed a preferential binding of BRD4 to the Myog promoter during C2C12 myoblast differentiation, co-incident with increased levels of H3K27 acetylation. These results have identified an essential role for BET proteins in the regulation of skeletal myogenesis, and assign distinct functions to BRD3 and BRD4.
format	article
author	Thomas C. Roberts Usue Etxaniz Alessandra Dall’Agnese Shwu-Yuan Wu Cheng-Ming Chiang Paul E. Brennan Matthew J. A. Wood Pier Lorenzo Puri
author_facet	Thomas C. Roberts Usue Etxaniz Alessandra Dall’Agnese Shwu-Yuan Wu Cheng-Ming Chiang Paul E. Brennan Matthew J. A. Wood Pier Lorenzo Puri
author_sort	Thomas C. Roberts
title	BRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis
title_short	BRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis
title_full	BRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis
title_fullStr	BRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis
title_full_unstemmed	BRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis
title_sort	brd3 and brd4 bet bromodomain proteins differentially regulate skeletal myogenesis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d950695199844891be7ec67ea14b2596
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_version_	1718395074214100992

BRD3 and BRD4 BET Bromodomain Proteins Differentially Regulate Skeletal Myogenesis

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