A hybrid mechanism of action for BCL6 in B cells defined by formation of functionally distinct complexes at enhancers and promoters
Date
2013
Authors
Hatzi, K.
Jiang, Y.
Huang, C.
Garrett-Bakelman, F.
Gearhart, M.D.
Giannopoulou, E.G.
Zumbo, P.
Kirouac, K.
Bhaskara, S.
Polo, J.M.
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Journal article
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Cell Reports, 2013; 4(3):578-588
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Katerina Hatzi, Yanwen Jiang, Chuanxin Huang, Francine Garrett-Bakelman, Micah D.Gearhart, Eugenia G.Giannopoulou
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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.
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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative WorksLicense, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source arecredited