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The Hiebert Laboratory

A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters.

AUTHORS

Hatzi KKaterina , Jiang Y Yanwen , Huang C Chuanxin , Garrett-Bakelman F Francine , Gearhart MD Micah D , Giannopoulou EG Eugenia G , Zumbo P Paul , Kirouac K Kevin , Bhaskara S Srividya , Polo JM Jose M , Kormaksson M Matthias , MacKerell AD Alexander D , Xue F Fengtian , Mason CE Christopher E , Hiebert SW Scott W , Prive GG Gilbert G , Cerchietti L Leandro , Bardwell VJ Vivian J , Elemento O Olivier , Melnick A Ari . Cell reports. 2013 8 15; 4(3). 578-88

ABSTRACT

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.

Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

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.

Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.