title: The Oncoprotein BRD4-NUT Generates Aberrant Histone Modification Patterns.
abstract: Defects in chromatin proteins frequently manifest in diseases. A striking case of a chromatin-centric disease is NUT-midline carcinoma (NMC), which is characterized by expression of NUT as a fusion partner most frequently with BRD4. ChIP-sequencing studies from NMC patients revealed that BRD4-NUT (B4N) covers large genomic regions and elevates transcription within these domains. To investigate how B4N modulates chromatin, we performed affinity purification of B4N when ectopically expressed in 293-TREx cells and quantified the associated histone posttranslational modifications (PTM) using proteomics. We observed significant enrichment of acetylation particularly on H3 K18 and of combinatorial patterns such as H3 K27 acetylation paired with K36 methylation. We postulate that B4N complexes override the preexisting histone code with new PTM patterns that reflect aberrant transcription and that epigenetically modulate the nucleosome environment toward the NMC state.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.|Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Barry M
authors.initials: BM
authors.lastname: Zee
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Dibona
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.|Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Artyom A
authors.initials: AA
authors.lastname: Alekseyenko
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: French
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.|Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Mitzi I
authors.initials: MI
authors.lastname: Kuroda
mesh_terms: D000107:Acetylation; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D015894:Genome, Human; D042421:Histone Code / Q000235:genetics; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009707:Nucleosomes / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics; D014158:Transcription, Genetic
chemical_list: C471990:BRD4-NUT fusion oncogene protein, human; D002843:Chromatin; D006657:Histones; D009687:Nuclear Proteins; D009707:Nucleosomes; D015514:Oncogene Proteins, Fusion