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Genes Dev. 2015 Jul 15;29(14):1507-23. doi: 10.1101/gad.267583.115.

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

Author information

1
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts, 02115, USA;
2
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
3
Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA;
4
Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA; Hematology/Oncology Program, Children's Hospital, Boston, Massachusetts 02115, USA; Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.

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:

BRD4; chromatin hyperacetylation; topological domains

PMID:
26220994
PMCID:
PMC4526735
DOI:
10.1101/gad.267583.115
[Indexed for MEDLINE]
Free PMC Article

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