title: The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains.
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.affiliation: 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;
authors.forename: Artyom A
authors.initials: AA
authors.lastname: Alekseyenko
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Erica M
authors.initials: EM
authors.lastname: Walsh
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Adlai R
authors.initials: AR
authors.lastname: Grayson
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Peter T
authors.initials: PT
authors.lastname: Hsi
authors.affiliation: 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.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Kharchenko
authors.affiliation: 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;
authors.forename: Mitzi I
authors.initials: MI
authors.lastname: Kuroda
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Christopher A
authors.initials: CA
authors.lastname: French
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000503:physiopathology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C000630260:NUTM1 protein, human
keywords: BRD4; chromatin hyperacetylation; topological domains