The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains
Open Access
- 15 July 2015
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 29 (14), 1507-1523
- https://doi.org/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.Keywords
Funding Information
- National Institutes of Health (GM101958, 2R01CA124633)
- Ellison Medical Foundation (AG-NS-0965-12)
- St. Baldrick's Foundation
- Institute of Chemistry and Cell Biology
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