The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains
- Artyom A. Alekseyenko1,2,7,
- Erica M. Walsh3,7,
- Xin Wang4,7,
- Adlai R. Grayson3,
- Peter T. Hsi3,
- Peter V. Kharchenko4,5,6,
- Mitzi I. Kuroda1,2 and
- Christopher A. French3
- 1Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 2Department of Genetics, Harvard Medical School, Boston, Massachusetts, 02115, USA;
- 3Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 4Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 5Hematology/Oncology Program, Children's Hospital, Boston, Massachusetts 02115, USA;
- 6Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA
- Corresponding authors: mkuroda{at}genetics.med.harvard.edu, cfrench{at}partners.org
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↵7 These authors contributed equally to this work.
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.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.267583.115.
- Received June 17, 2015.
- Accepted June 30, 2015.
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