Brd2 is a member of the bromodomain extra terminal (BET) protein family, which consists of four chromatin-interacting proteins that regulate gene expression. Each BET protein contains two N-terminal bromodomains, which recognize acetylated histones, and the C-terminal protein-protein interaction domain. Using a genome-wide screen, we identify 1450 genes whose transcription is regulated by Brd2. In addition, almost 290 genes change their alternative splicing pattern upon Brd2 depletion. Brd2 is specifically localized at promoters of target genes, and our data show that Brd2 interaction with chromatin cannot be explained solely by histone acetylation. Using coimmunoprecipitation and live-cell imaging, we show that the C-terminal part is crucial for Brd2 association with chromatin. Live-cell microscopy also allows us to map the average binding time of Brd2 to chromatin and quantify the contributions of individual Brd2 domains to the interaction with chromatin. Finally, we show that bromodomains and the C-terminal domain are equally important for transcription and splicing regulation, which correlates with the role of these domains in Brd2 binding to chromatin.

Department of RNA Biology Institute of Molecular Genetics Academy of Sciences of the Czech Republic Prague 142 20 Czech Republic Institute of Microbiology Academy of Sciences of the Czech Republic Prague 142 20 Czech Republic Max Planck Institute for Molecular Cell Biology and Genetics Dresden 01307 Germany J Heyrovsky Institute of Physical Chemistry Academy of Sciences of the Czech Republic Prague 182 23 Czech Republic

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TALE-directed local modulation of H3K9 methylation shapes exon recognition

CRE promoter sites modulate alternative splicing via p300-mediated histone acetylation