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

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TitleA hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters.
Publication TypeJournal Article
Year of Publication2013
AuthorsHatzi, K, Jiang, Y, Huang, C, Garrett-Bakelman, F, Gearhart, MD, Giannopoulou, EG, Zumbo, P, Kirouac, K, Bhaskara, S, Polo, JM, Kormaksson, M, Mackerell, AD, Xue, F, Mason, CE, Hiebert, SW, Privé, GG, Cerchietti, L, Bardwell, VJ, Elemento, O, Melnick, A
JournalCell Rep
Volume4
Issue3
Pagination578-88
Date Published2013 Aug 15
ISSN2211-1247
KeywordsAnimals, B-Lymphocytes, Cell Line, Tumor, DNA-Binding Proteins, Heterografts, Humans, Lymphoma, Large B-Cell, Diffuse, Mice, Models, Molecular, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-6, Signal Transduction
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.

DOI10.1016/j.celrep.2013.06.016
Alternate JournalCell Rep
PubMed ID23911289
PubMed Central IDPMC3854650
Grant ListR01 CA071540 / CA / NCI NIH HHS / United States
R01 CA104348 / CA / NCI NIH HHS / United States
R01 CA143032 / CA / NCI NIH HHS / United States
R01 CA164605 / CA / NCI NIH HHS / United States