CtBP is an essential corepressor for BCL6 autoregulation

Department of Cell Biology, and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA

^* To whom correspondence should be addressed. Email: hye{at}aecom.yu.edu.

	Abstract

The transcription repressor BCL6 plays an essential role in the formation and function of germinal center (GC). While normal B cells promptly shut off BCL6 when they exit GC, many GC-derived B cell lymphomas sustain BCL6 expression through chromosomal translocations and activating mutations. We have previously shown that a common effect of lymphoma-associated BCL6 gene alterations is to bypass a negative autoregulatory loop that controls its transcription. In this study, we report that BCL6 autoregulation is independent of several known corepressor complexes including SMRT, NCOR, BCOR, and MTA3/NuRD. Furthermore, we show that BCL6 can interact with the CtBP (C-terminal binding protein) corepressor both in vitro and in vivo, and that CtBP is recruited by BCL6 to its 5' regulatory region. In lymphoma cell lines carrying BCL6 translocations, siRNA-mediated CtBP knock-down selectively relieved the previously silenced wt BCL6 allele but not the translocated alleles which are driven by heterologous promoters. These results demonstrate that CtBP is a novel BCL6 corepressor and suggest that a unique corepressor requirement for BCL6 autoregulation may allow GC B cells to differentially control the expression of BCL6 and other BCL6 target genes in response to environmental stimuli during the GC stage of B cell development.