Convergence of Developmental and Oncogenic Signaling Pathways at Transcriptional Super-Enhancers

被引：377

作者：

Hnisz, Denes ^{[1
]}

Schuijers, Jurian ^{[1
]}

Lin, Charles Y. ^{[2
]}

Weintraub, Abraham S. ^{[1
,3
]}

Abraham, Brian J. ^{[1
]}

Lee, Tong Ihn ^{[1
]}

Bradner, James E. ^{[2
]}

Young, Richard A. ^{[1
,3
]}

机构：

[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] MIT, Dept Biol, Cambridge, MA 02139 USA

来源：

MOLECULAR CELL | 2015年 / 58卷 / 02期

关键词：

CELL IDENTITY; GENE-EXPRESSION; STEM-CELLS; INFLAMMATION; TARGET; MYC;

D O I：

10.1016/j.molcel.2015.02.014

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Super-enhancers and stretch enhancers (SEs) drive expression of genes that play prominent roles in normal and disease cells, but the functional importance of these clustered enhancer elements is poorly understood, so it is not clear why genes key to cell identity have evolved regulation by such elements. Here, we show that SEs consist of functional constituent units that concentrate multiple developmental signaling pathways at key pluripotency genes in embryonic stem cells and confer enhanced responsiveness to signaling of their associated genes. Cancer cells frequently acquire SEs at genes that promote tumorigenesis, and we show that these genes are especially sensitive to perturbation of oncogenic signaling pathways. Super-enhancers thus provide a platform for signaling pathways to regulate genes that control cell identity during development and tumorigenesis.

引用

页码：362 / 370

页数：9

共 38 条

[1] The hypersensitive sites of the murine β-globin locus control region act independently to affect nuclear localization and transcriptional elongation [J].

Bender, M. A. ;

Ragoczy, Tobias ;

Lee, Jongjoo ;

Byron, Rachel ;

Telling, Agnes ;

Dean, Ann ;

Groudine, Mark .

BLOOD, 2012, 119 (16) :3820-3827

[2] NF-κB Directs Dynamic Super Enhancer Formation in Inflammation and Atherogenesis [J].

Brown, Jonathan D. ;

Lin, Charles Y. ;

Duan, Qiong ;

Griffin, Gabriel ;

Federation, Alexander J. ;

Paranal, Ronald M. ;

Bair, Steven ;

Newton, Gail ;

Lichtman, Andrew H. ;

Kung, Andrew L. ;

Yang, Tianlun ;

Wang, Hong ;

Luscinskas, Francis W. ;

Croce, Kevin J. ;

Bradner, James E. ;

Plutzky, Jorge .

MOLECULAR CELL, 2014, 56 (02) :219-231

[3] Functional and Mechanistic Diversity of Distal Transcription Enhancers [J].

Bulger, Michael ;

Groudine, Mark .

CELL, 2011, 144 (03) :327-339

[4] Discovery and Characterization of Super-Enhancer-Associated Dependencies in Diffuse Large B Cell Lymphoma [J].

Chapuy, Bjoern ;

McKeown, Michael R. ;

Lin, Charles Y. ;

Monti, Stefano ;

Roemer, Margaretha G. M. ;

Qi, Jun ;

Rahl, Peter B. ;

Sun, Heather H. ;

Yeda, Kelly T. ;

Doench, John G. ;

Reichert, Elaine ;

Kung, Andrew L. ;

Rodig, Scott J. ;

Young, Richard A. ;

Shipp, Margaret A. ;

Bradner, James E. .

CANCER CELL, 2013, 24 (06) :777-790

[5] Integration of external signaling pathways with the core transcriptional network in embryonic stem cells [J].

Chen, Xi ;

Xu, Han ;

Yuan, Ping ;

Fang, Fang ;

Huss, Mikael ;

Vega, Vinsensius B. ;

Wong, Eleanor ;

Orlov, Yuriy L. ;

Zhang, Weiwei ;

Jiang, Jianming ;

Loh, Yuin-Han ;

Yeo, Hock Chuan ;

Yeo, Zhen Xuan ;

Narang, Vipin ;

Govindarajan, Kunde Ramamoorthy ;

Leong, Bernard ;

Shahab, Atif ;

Ruan, Yijun ;

Bourque, Guillaume ;

Sung, Wing-Kin ;

Clarke, Neil D. ;

Wei, Chia-Lin ;

Ng, Huck-Hui .

CELL, 2008, 133 (06) :1106-1117

[6] Wnt/β-Catenin Signaling and Disease [J].

Clevers, Hans ;

Nusse, Roel .

CELL, 2012, 149 (06) :1192-1205

[7] Control of Cell Identity Genes Occurs in Insulated Neighborhoods in Mammalian Chromosomes [J].

Dowen, Jill M. ;

Fan, Zi Peng ;

Hnisz, Denes ;

Ren, Gang ;

Abraham, Brian J. ;

Zhang, Lyndon N. ;

Weintraub, Abraham S. ;

Schuijers, Jurian ;

Lee, Tong Ihn ;

Zhao, Keji ;

Young, Richard A. .

CELL, 2014, 159 (02) :374-387

[8] An integrated encyclopedia of DNA elements in the human genome [J].

Dunham, Ian ;

Kundaje, Anshul ;

Aldred, Shelley F. ;

Collins, Patrick J. ;

Davis, CarrieA. ;

Doyle, Francis ;

Epstein, Charles B. ;

Frietze, Seth ;

Harrow, Jennifer ;

Kaul, Rajinder ;

Khatun, Jainab ;

Lajoie, Bryan R. ;

Landt, Stephen G. ;

Lee, Bum-Kyu ;

Pauli, Florencia ;

Rosenbloom, Kate R. ;

Sabo, Peter ;

Safi, Alexias ;

Sanyal, Amartya ;

Shoresh, Noam ;

Simon, Jeremy M. ;

Song, Lingyun ;

Trinklein, Nathan D. ;

Altshuler, Robert C. ;

Birney, Ewan ;

Brown, James B. ;

Cheng, Chao ;

Djebali, Sarah ;

Dong, Xianjun ;

Dunham, Ian ;

Ernst, Jason ;

Furey, Terrence S. ;

Gerstein, Mark ;

Giardine, Belinda ;

Greven, Melissa ;

Hardison, Ross C. ;

Harris, Robert S. ;

Herrero, Javier ;

Hoffman, Michael M. ;

Iyer, Sowmya ;

Kellis, Manolis ;

Khatun, Jainab ;

Kheradpour, Pouya ;

Kundaje, Anshul ;

Lassmann, Timo ;

Li, Qunhua ;

Lin, Xinying ;

Marinov, Georgi K. ;

Merkel, Angelika ;

Mortazavi, Ali .

NATURE, 2012, 489 (7414) :57-74

[9] Genetic and epigenetic fine mapping of causal autoimmune disease variants [J].

Farh, Kyle Kai-How ;

Marson, Alexander ;

Zhu, Jiang ;

Kleinewietfeld, Markus ;

Housley, William J. ;

Beik, Samantha ;

Shoresh, Noam ;

Whitton, Holly ;

Ryan, Russell J. H. ;

Shishkin, Alexander A. ;

Hatan, Meital ;

Carrasco-Alfonso, Marlene J. ;

Mayer, Dita ;

Luckey, C. John ;

Patsopoulos, Nikolaos A. ;

De Jager, Philip L. ;

Kuchroo, Vijay K. ;

Epstein, Charles B. ;

Daly, Mark J. ;

Hafler, David A. ;

Bernstein, Bradley E. .

NATURE, 2015, 518 (7539) :337-343

[10] Phenotypic robustness conferred by apparently redundant transcriptional enhancers [J].

Frankel, Nicolas ;

Davis, Gregory K. ;

Vargas, Diego ;

Wang, Shu ;

Payre, Francois ;

Stern, David L. .

NATURE, 2010, 466 (7305) :490-U8

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