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

Academic Article

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.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Author List

  • Alekseyenko AA; Walsh EM; Wang X; Grayson AR; Hsi PT; Kharchenko PV; Kuroda MI; French CA
  • Start Page

  • 1507
  • End Page

  • 1523
  • Volume

  • 29
  • Issue

  • 14