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. Epub 2013 Aug 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / physiology*
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Heterografts
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Mice
  • Models, Molecular
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-bcl-6
  • Signal Transduction

Substances

  • BCL6 protein, human
  • Bcl6 protein, mouse
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins c-bcl-6

Associated data

  • GEO/GSE29282
  • GEO/GSE43350