The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor

Jotin Marango, Manabu Shimoyama, Hitomi Nishio, Julia A. Meyer, Dong Joon Min, Andres Sirulnik, Yolanda Martinez-Martinez, Marta Chesi, P. Leif Bergsagel, Ming Ming Zhou, Samuel Waxman, Boris A. Leibovitch, Martin J. Walsh, Jonathan D. Licht

Research output: Contribution to journalArticle

142 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3145-3154
Number of pages10
JournalBlood
Volume111
Issue number6
DOIs
StatePublished - Mar 15 2008

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Marango, J., Shimoyama, M., Nishio, H., Meyer, J. A., Min, D. J., Sirulnik, A., Martinez-Martinez, Y., Chesi, M., Bergsagel, P. L., Zhou, M. M., Waxman, S., Leibovitch, B. A., Walsh, M. J., & Licht, J. D. (2008). The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood, 111(6), 3145-3154. https://doi.org/10.1182/blood-2007-06-092122