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 M. Polo, Matthias Kormaksson, Alexander D. MacKerell, Fengtian Xue, Christopher E. Mason, Scott W. Hiebert, Gilbert G. Prive, Leandro Cerchietti, Vivian J. Bardwell, Olivier Elemento, Ari Melnick

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

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 languageEnglish (US)
Pages (from-to)578-588
Number of pages11
JournalCell reports
Volume4
Issue number3
DOIs
StatePublished - 2013

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