title: The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor.
abstract: MMSET, identified by its fusion to the IgH locus in t(4;14)-associated multiple myeloma, possesses domains found within chromatin regulators, including the SET domain. MMSET protein is overexpressed and highly associated with chromatin in myeloma cell lines carrying t(4;14). MMSET possesses methyltransferase activity for core histone H3 lysine 4 and histone 4 lysine 20, whereas MMSET made in cells only modified H4. Segments of MMSET fused to the Gal4 DNA binding domain repressed transcription of a chromatin-embedded Gal4 reporter gene. MMSET-mediated repression was associated with increased H4K20 methylation gene and loss of histone acetylation. Consistent with this repressive activity, MMSET could form a complex with HDAC1 and HDAC2, mSin3a, and the histone demethylase LSD1, suggesting that it is a component of corepressor complexes. Furthermore, MMSET coexpression enhances HDAC1- and HDAC2-mediated repression in transcriptional reporter assays. Finally, shRNA-mediated knockdown of MMSET compromised viability of a myeloma cell line, suggesting a biologic role for the protein in malignant cell growth. Collectively, these data suggest that, by acting directly as a modifier of chromatin as well as through binding of other chromatin-modifying enzymes, MMSET influences gene expression and potentially acts as a pathogenic agent in multiple myeloma.
authors.affiliation: Division of Hematology/Oncology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Jotin
authors.initials: J
authors.lastname: Marango
authors.forename: Manabu
authors.initials: M
authors.lastname: Shimoyama
authors.forename: Hitomi
authors.initials: H
authors.lastname: Nishio
authors.forename: Julia A
authors.initials: JA
authors.lastname: Meyer
authors.forename: Dong-Joon
authors.initials: DJ
authors.lastname: Min
authors.forename: Andres
authors.initials: A
authors.lastname: Sirulnik
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Martinez-Martinez
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
authors.forename: Samuel
authors.initials: S
authors.lastname: Waxman
authors.forename: Boris A
authors.initials: BA
authors.lastname: Leibovitch
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Walsh
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Licht
mesh_terms: D000818:Animals; D002384:Catalysis; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D002470:Cell Survival; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011817:Rabbits; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D006657:Histones; D007527:Isoenzymes; D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human