BRD4 and MYC—clarifying regulatory specificity

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Science  18 May 2018:
Vol. 360, Issue 6390, pp. 713-714
DOI: 10.1126/science.aat6664

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The transcriptional output of cells is governed by the interplay among sequence-specific transcription factors (TFs), epigenetic DNA and chromatin modifications, and their writers, readers, and erasers, along with the basal transcriptional machinery and RNA polymerase II (Pol2). Assessing the contribution of individual factors to specific transcriptional programs is an essential albeit elusive goal, as exemplified by studies of the chromatin-associated factor BRD4 (a BET family member) (1) or the oncogenic TF MYC (2). BET proteins interact with acetylated histones in active regulatory domains (promoters and enhancers) and promote Pol2 activity. Despite the general nature of this mechanism, BET inhibitors (BETis) have shown selective effects on gene expression—in particular, suppression of MYC and other oncogenes in tumor cells (1). MYC is a sequence-specific DNA-binding protein that has been proposed to function either as a selective regulator (24) or as a general activator (“amplifier”) of transcriptional activity (5, 6). Determining regulatory specificities is hampered by the need to identify productive DNA-binding events and to distinguish direct from indirect transcriptional responses. On page 800 of this issue, Muhar et al. (7) provide unprecedented resolution on the regulatory roles of MYC and BRD4, improving our understanding of these cancer-associated TFs.