Promoter-specific mechanisms of repression: BCL6 negative autoregulation

Abstract

BCL6 is a BTB/POZ zinc finger transcription factor that plays important roles in lymphomagenesis, B cell development and T-helper cell differentiation. High level BCL6 expression is required for germinal center formation and T-cell dependent antibody response. While normal B cells promptly shut off BCL6 when they leave germinal centers, many B cell lymphomas, particularly diffuse large B cell lymphomas, sustain BCL6 expression through chromosomal translocations and activating mutations. Both bypass a negative autoregulation mechanism governing BCL6 transcription.;BCL6 carries out its biological function by repressing a cohort of target genes that is cell-type specific. Its repression activity depends on the recruitment of co-repressors such as SMRT, BCoR and NuRD to target gene promoters. We hypothesized that the promoter specific nature of BCL6 repression is a result of (a) collaboration with other sequence-specific transcription factors and (b) differential recruitment of co-repressor complexes to target gene promoters.;In the current model, BCL6 represses transcription by binding to specific DNA sequences and subsequently recruiting chromatin remodeling complexes to impose a closed chromatin conformation. We used a mutant version of BCL6, called BCL6Cmpd, to study the role of trans factors in defining promoter-specificity of BCL6 repression. BCL6Cmpd is largely inactive due to its inability to recruit known co-repressors. Surprisingly, however, it retains full activity on the BCL6 promoter which undergoes negative autoregulation in a variety of cell types. This suggested that BCL6 autoregulation requires a novel co-repressor(s). We took a candidate approach focusing on the co-repressor CtBP, which in Drosophila genetically and physically interacts with the BTB/POZ zinc finger protein Ttk69. Our data demonstrated that in B cells, through protein-protein interaction, CtBP is recruited to the BCL6 exon 1 where it is required for BCL6 autoregulation.;In summary, we find that the BCL6 promoter is unique among BCL6 target genes. Its distinct co-repressor requirement may allow germinal center B cells to buildup abundant BCL6 while efficiently inhibiting other BCL6 target genes. This investigation reveals a novel BCL6 co-repressor and provides new mechanistic insights into BCL6 autoregulation which is targeted in nearly half of diffuse large B cell lymphomas.