The bromodomain inhibitor JQ1 is a molecular glue targeting centromeres

Abstract

Centromeres are essential for cell proliferation and a promising target for anti-cancer therapies, yet no drugs have been identified that specifically target centromeric chromatin. To identify candidates, we analysed chromatin proteins at repetitive loci using a novel big-data approach and discovered the bromodomain protein BRD4 localises to centromeres, a localisation enhanced by the bromodomain inhibitor JQ1. While bromodomain inhibitors typically prevent BRD4 from binding chromatin, we found that JQ1 stabilises an interaction between BRD4 and the centromere protein CENP-B. Degradation of BRD4 caused centromere cohesion defects, whereas JQ1-treatment preserved centromere structure in a CENP-B dependent manner. Strikingly, JQ1-resistant cells became reliant on CENP-B for proliferation. Our results identify a non-canonical role for BRD4 in centromere cohesion and establish JQ1 as a molecular-glue targeting centromeric chromatin.

Genomic context-dependent histone H3K36 methylation by three Drosophila methyltransferases and implications for dedicated chromatin readers

“…We found that K36me3 partitions between eu- and heterochromatin. The presence of K36me3, a mark globally associated with active chromatin, at H3K9-methylated heterochromatin has also been observed in other studies ( 3 , 84 ) and been described in human datasets ( 93 , 94 ). Such overlap of active with more repressive chromatin features may not simply be due to population heterogeneity since engineered dual readers validated the existence of such dual domains ( 84 , 95 ) and have been proposed to bookmark poised enhancers genome-wide in mouse ( 84 ).…”