| The BCL6 protooncogene encodes a DNA-binding transcriptional repressor, which was identified due to its involvement in chromosomal translocations associated with the pathogenesis of B cell lymphoma. BCL6 is expressed in germinal center (GC) B cells, and is required for the formation of GC, where it represses transcription of genes controlling proliferation, activation, differentiation and apoptosis. The BCL6 repressive function requires two non-contiguous domains, which have been shown to recruit hi stone-deacetylase (HDAC) containing complexes. I have found that the transcriptional coactivator p300 binds and acetylates BCL6 at specific lysine residues in vivo. Notably, p300-mediated acetylation is associated with inactivation of BCL6 transrepressor function in transient transfection/luciferase reporter assays in 293T cells. We show that acetylated BCL6 associates with HDAC2, suggesting this as the mechanism for its p300-mediated inactivation. Importantly, the association of BCL6 with HDAC2 as well as its acetylation upon treatment with HDAC inhibitors was confirmed in native B cells under physiologic conditions. These results indicate that p300-mediated acetylation may be a novel pathway in the regulation of BCL6 function as a transcriptional repressor in B cells. Since BCL6 controls apoptosis, its inactivation by treatment with HDAC inhibitors may be exploitable as a therapeutic approach. More generally, the finding of acetylation-mediated inhibition of a transcriptional repressor provides a new paradigm by which acetylation can promote transcription not only by modifying histones and activating transcriptional activators (e.g. p53, GATA-1), but also by inhibiting transcriptional repressors. |
