Selective Disruption of Core Regulatory Transcription [RNA-seq]

Activation of identity determining transcription factors (TFs), or core regulatory TFs, is governed by cell-type specific enhancers, an important subset of these being super enhancers (SEs). This mechanism is distinct from constitutive expression of housekeeping genes. The characterization of drug-like small molecules to selectively inhibit core regulatory circuitry is of high interest for treatment of cancers, which are addicted to core regulatory TF function at SEs. Surprisingly, we find histone deacetylases (HDAC) to be an indispensable component of SE-driven transcription. While histone acetylation is a marker for active genes, over accumulation of acetylation selectively halts core regulatory transcription. We show this conundrum may in part be explained by a SE-specific need for resetting histones to maintain SE boundaries, to facilitate enhancer-promoter looping and high levels of transcription. Overall design: RNA-seq data for FP-RMS cells treated with various concentrations of various small molecules modulators of epigenetic processes.

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Gryder BE, Wu L, Woldemichael GM, Pomella S, Quinn TR, Park PMC, Cleveland A, Stanton BZ, Song Y, Rota R, Wiest O, Yohe ME, Shern JF, Qi J, Khan J