The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains

May 1131, 11018

brain

Authors

Alekseyenko AA†, Walsh EM†, Wang X†, Grayson AR, Hsi PT, Kharchenko PV, Kuroda MI, and French CA

Genes Dev 2015, doi:10.1101/gad.267583.115.

Abstract

NUT midline carcinoma (NMC), a subtype of squamous cell cancer, is one of the most aggressive human solid malignancies known. NMC is driven by the creation of a translocation oncoprotein, BRD4-NUT, which blocks differentiation and drives growth of NMC cells. BRD4-NUT forms distinctive nuclear foci in patient tumors, which we found correlate with ∼100 unprecedented, hyperacetylated expanses of chromatin that reach up to 2 Mb in size.

These “megadomains” appear to be the result of aberrant, feed-forward loops of acetylation and binding of acetylated histones that drive transcription of underlying DNA in NMC patient cells and naïve cells induced to express BRD4-NUT. Megadomain locations are typically cell lineage-specific; however, the cMYC and TP63 regions are targeted in all NMCs tested and play functional roles in tumor growth. Megadomains appear to originate from select pre-existing enhancers that progressively broaden but are ultimately delimited by topologically associating domain (TAD) boundaries. Therefore, our findings establish a basis for understanding the powerful role played by large-scale chromatin organization in normal and aberrant lineage-specific gene transcription.

Keyword

BRD4; chromatin hyperacetylation; topological domains

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