ZEB1 and CtBP form a repressive complex at a distal promoter element of the BCL6 locus
Résumé
BCL6 is essential for normal antibody responses and is highly expressed in germinal centre B-cells. Constitutive expression due to chromosomal translocations or mutations of cis-acting regulatory elements contributes to diffuse large B-cell lymphoma. BCL6 expression is, therefore, tightly regulated in a lineage and developmental stage specific manner and disruption of normal controls can contribute to lymphomagenesis. In order to discover potential cis-acting control regions we carried out DNase I hypersensitive site mapping. Gel shift assays and chromatin immuno-precipitation of the core region of a hypersensitive site 4.4kb upstream of BCL6 transcription initiation (HSS-4.4) showed an E-box element binding ZEB1 and the co-repressor CtBP. As compared to peripheral blood B-cells, ZEB1, a two-handed zinc finger transcriptional repressor, is expressed at relatively low levels in germinal centre cells whereas BCL6 has the opposite pattern of expression. Transfection of ZEB1 cDNA caused a reduction in BCL6 expression and a mutated ZEB1, incapable of binding CtBP, lacked this effect. siRNA mediated knockdown of ZEB1 or CtBP produced an increase in BCL6 mRNA. We propose that HSS-4.4 is a distal promoter element binding a repressive complex consisting of ZEB1 and CtBP. CtBP is ubiquitously expressed and our results suggest regulation of ZEB1 is required for control of BCL6 expression.
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