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 conformationthrough 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
Original language | English (US) |
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Pages (from-to) | 578-588 |
Number of pages | 11 |
Journal | Cell reports |
Volume | 4 |
Issue number | 3 |
DOIs | |
State | Published - 2013 |
Bibliographical note
Funding Information:We would like to thank the members of the Melnick lab for their support and constructive discussions, Grant Barish and Ron Evans for providing the NCOR antibody used in this study, Mariano Cardenas and Connie Marie Corcoran for technical assistance, and the Weill Cornell Epigenomics Core for high-throughput data processing. This work was supported by NCI R01 CA104348 (A.M.), NCI R01 CA071540 (V.B.), and NSF CAREER grant 1054964 (O.E.). A.M. is supported by the Chemotherapy Foundation and the Burroughs Wellcome Foundation. F.G.B. is supported by a Sass Foundation Judah Folkman Fellowship. L.C. is a Raymond and Beverly Sackler Scholar. J.M.P. is supported by the NHMRC and Monash Larkins Program. G.G.P. and K.K. were funded by the CCSRI. This research was also made possible by the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College.