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

Katerina Hatzi, Yanwen Jiang, Chuanxin Huang, Francine Garrett-Bakelman, Micah D Gearhart, Eugenia G Giannopoulou, Paul Zumbo, Kevin Kirouac, Srividya Bhaskara, Jose Maria Polo, Matthias Kormaksson, Alexander D MacKerell Jr, Fengtian Xue, Christopher E Mason, Scott W Hiebert, Gilbert G Prive, Leandro Cerchietti, Vivian J Bardwell, Olivier Elemento, Ari Melnick

Research output: Contribution to journalArticleResearchpeer-review

112 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)578 - 588
Number of pages11
JournalCell Reports
Volume4
Issue number3
DOIs
Publication statusPublished - 2013

Cite this