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

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

  • Cell Rep. 2013 Aug 15;4(3):578-88. doi: 10.1016/j.celrep.2013.06.016.
Katerina Hatzi 1,  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 Jr,  Fengtian Xue,  Christopher E Mason,  Scott W Hiebert,  Gilbert G Prive,  Leandro Cerchietti,  Vivian J Bardwell,  Olivier Elemento,  Ari Melnick
Affiliations

Affiliation

  • 1 Division of Hematology and Medical Oncology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
PMID: 23911289 DOI: 10.1016/j.celrep.2013.06.016
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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