Control of Embryonic Stem Cell Identity by BRD4-Dependent Transcriptional Elongation of Super-Enhancer-Associated Pluripotency Genes

被引：175

作者：

Di Micco, Raffaella ^{[1
,2
,3
]}

Fontanals-Cirera, Barbara ^{[1
,2
,3
]}

Low, Vivien ^{[1
,2
,3
]}

Ntziachristos, Panagiotis ^{[1
,2
,3
,4
,5
]}

Yuen, Stephanie K. ^{[1
,2
,3
]}

Lovell, Claudia D. ^{[1
,2
,3
]}

Dolgalev, Igor ^{[6
]}

Yonekubo, Yoshiya ^{[1
,2
,3
]}

Zhang, Guangtao ^{[7
]}

Rusinova, Elena ^{[7
]}

Gerona-Navarro, Guillermo ^{[7
]}

Canamero, Marta ^{[8
]}

Ohlmeyer, Michael ^{[7
]}

Aifantis, Iannis ^{[1
,2
,3
,4
,5
]}

Zhou, Ming-Ming ^{[7
]}

Tsirigos, Aristotelis ^{[1
,2
,9
]}

Hernando, Eva ^{[1
,2
,3
]}

机构：

[1] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA

[2] Perlmutter Canc Ctr, New York, NY 10016 USA

[3] NYU, Langone Med Ctr, Helen L & Martin S Kimmel Ctr Stem Cell Biol, New York, NY 10016 USA

[4] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA

[5] NYU, Sch Med, Inst Canc, New York, NY 10016 USA

[6] NYU Med Ctr, Off Collaborat Sci, Genome Technol Ctr, New York, NY 10016 USA

[7] Icahn Sch Med Mt Sinai, Dept Struct & Chem Biol, New York, NY 10029 USA

[8] Ctr Nacl Invest Oncol, Biotechnol Program, Histopathol Core Unit, Madrid 28029, Spain

[9] NYU, Sch Med, Ctr Hlth Informat & Bioinformat, New York, NY 10016 USA

来源：

CELL REPORTS | 2014年 / 9卷 / 01期

关键词：

BET BROMODOMAINS; RNAI SCREEN; HISTONE ACETYLTRANSFERASE; SELECTIVE-INHIBITION; SELF-RENEWAL; PROTEIN BRD4; C-MYC; CHROMATIN; COMPLEX; DIFFERENTIATION;

D O I：

10.1016/j.celrep.2014.08.055

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Transcription factors and chromatin-remodeling complexes are key determinants of embryonic stem cell (ESC) identity. Here, we demonstrate that BRD4, a member of the bromodomain and extraterminal domain (BET) family of epigenetic readers, regulates the self-renewal ability and pluripotency of ESCs. BRD4 inhibition resulted in induction of epithelial-to-mesenchymal transition (EMT) markers and commitment to the neuroectodermal lineage while reducing the ESC multidifferentiation capacity in teratoma assays. BRD4 maintains transcription of core stem cell genes such as OCT4 and PRDM14 by occupying their super-enhancers (SEs), large clusters of regulatory elements, and recruiting to them Mediator and CDK9, the catalytic subunit of the positive transcription elongation factor b (P-TEFb), to allow Pol-II-dependent productive elongation. Our study describes a mechanism of regulation of ESC identity that could be applied to improve the efficiency of ESC differentiation.

引用

页码：234 / 247

页数：14

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