A Hybrid Mechanism of Action for BCL6 in B Cells Defined by Formation of Functionally Distinct Complexes at Enhancers and Promoters

被引：150

作者：

Hatzi, Katerina ^{[1
]}

Jiang, Yanwen ^{[1
,2
]}

Huang, Chuanxin ^{[1
]}

Garrett-Bakelman, Francine ^{[1
]}

Gearhart, Micah D. ^{[3
,4
]}

Giannopoulou, Eugenia G. ^{[2
]}

Zumbo, Paul ^{[2
]}

Kirouac, Kevin ^{[5
]}

Bhaskara, Srividya ^{[6
]}

Polo, Jose M. ^{[7
,8
]}

Kormaksson, Matthias ^{[9
]}

MacKerell, Alexander D., Jr. ^{[10
]}

Xue, Fengtian ^{[10
]}

Mason, Christopher E. ^{[2
]}

Hiebert, Scott W. ^{[6
]}

Prive, Gilbert G. ^{[5
]}

Cerchietti, Leandro ^{[1
]}

Bardwell, Vivian J. ^{[3
,4
]}

Elemento, Olivier ^{[2
]}

Melnick, Ari ^{[1
]}

机构：

[1] Cornell Univ, Weill Cornell Med Coll, Div Hematol & Med Oncol, New York, NY 10065 USA

[2] Cornell Univ, Inst Computat Biomed, Weill Cornell Med Coll, New York, NY 10065 USA

[3] Univ Minnesota, Mason Canc Ctr, Ctr Dev Biol, Minneapolis, MN 55455 USA

[4] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA

[5] Ontario Canc Inst, Div Canc Genom & Prote, Toronto, ON M5G 1L7, Canada

[6] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA

[7] Monash Univ, Australian Regenerat Med Inst, Clayton, Vic 3800, Australia

[8] Monash Univ, Dept Anat & Dev Biol, Clayton, Vic 3800, Australia

[9] Cornell Univ, Weill Cornell Med Coll, Div Biostat & Epidemiol, New York, NY 10065 USA

[10] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA

来源：

CELL REPORTS | 2013年 / 4卷 / 03期

基金：

澳大利亚国家健康与医学研究理事会; 美国国家科学基金会;

关键词：

LYMPHOMA-CELLS; BTB DOMAIN; IN-VIVO; BIOCHEMICAL-MECHANISMS; REPRESSION; COREPRESSOR; EXPRESSION; DIFFERENTIATION; INFLAMMATION; AUTOREGULATION;

D O I：

10.1016/j.celrep.2013.06.016

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The BCL6 transcriptional repressor is required for the development of germinal center (GC) B cells and diffuse large B cell lymphomas (DLBCLs). Although BCL6 can recruit multiple corepressors, its transcriptional repression mechanism of action in normal and malignant B cells is unknown. We find that in B cells, BCL6 mostly functions through two independent mechanisms that are collectively essential to GC formation and DLBCL, both mediated through its N-terminal BTB domain. These are (1) the formation of a unique ternary BCOR-SMRT complex at promoters, with each corepressor binding to symmetrical sites on BCL6 homodimers linked to specific epigenetic chromatin features, and (2) the "toggling" of active enhancers to a poised but not erased conformation through SMRT-dependent H3K27 deacetylation, which is mediated by HDAC3 and opposed by p300 histone acetyltransferase. Dynamic toggling of enhancers provides a basis for B cells to undergo rapid transcriptional and phenotypic changes in response to signaling or environmental cues.

引用

页码：578 / 588

页数：11

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