BCL6promoter interacts with far upstream sequences with greatly enhanced activating histone modifications in germinal center B cells

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Abstract
BCL6encodes a transcriptional repressor that is essential for the germinal center (GC) reaction and important in lymphomagenesis. Although its promoter has been well studied, little is known concerning its possible regulation by more distal elements. To gain such information, we mapped critical histone modifications associated with active transcription withinBCL6as well as far upstream sequences at nucleosomal resolution in B-cell lines and in normal naive and GC B cells. Promoter-associated and intronic CpG islands (CGIs) inBCL6showed a reciprocal pattern of histone modifications. Gene expression correlated with a paradoxical loss from the intronic CGI of histone H3 lysine-4 trimethylation, normally associated with transcription, suggesting that the intronic CGI may interfere with transcription. In an ∼110-kb region extending 150–260 kb upstream ofBCL6, highly active histone modifications were present only in normal GC B cells and a GC B-cell line; this region overlaps with an alternative breakpoint region for chromosomal translocations and contains a GC-specific noncoding RNA gene. By chromosome conformation capture, we determined that theBCL6promoter interacts with this distant upstream region. It is likely that transcriptional enhancers in this region activateBCL6and overcome strong autorepression in GC B cells.

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