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, Peter Leif Bergsagel, Ming Ming Zhou, Samuel Waxman, Boris A. Leibovitch, Martin J. Walsh, Jonathan D. Licht

Research output: Contribution to journalArticle

135 Citations (Scopus)

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

Fingerprint

Co-Repressor Proteins
Chromatin
Histones
Proteins
Multiple Myeloma
Lysine
Genes
Histone Demethylases
Cells
Cell Line
Acetylation
Methylation
Methyltransferases
Cell growth
Transcription
Reporter Genes
Gene expression
Small Interfering RNA
Assays
Fusion reactions

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Marango, J., Shimoyama, M., Nishio, H., Meyer, J. A., Min, D. J., Sirulnik, A., ... 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

The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. / Marango, Jotin; Shimoyama, Manabu; Nishio, Hitomi; Meyer, Julia A.; Min, Dong Joon; Sirulnik, Andres; Martinez-Martinez, Yolanda; Chesi, Marta; Bergsagel, Peter Leif; Zhou, Ming Ming; Waxman, Samuel; Leibovitch, Boris A.; Walsh, Martin J.; Licht, Jonathan D.

In: Blood, Vol. 111, No. 6, 15.03.2008, p. 3145-3154.

Research output: Contribution to journalArticle

Marango, J, Shimoyama, M, Nishio, H, Meyer, JA, Min, DJ, Sirulnik, A, Martinez-Martinez, Y, Chesi, M, Bergsagel, PL, Zhou, MM, Waxman, S, Leibovitch, BA, Walsh, MJ & Licht, JD 2008, 'The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor', Blood, vol. 111, no. 6, pp. 3145-3154. https://doi.org/10.1182/blood-2007-06-092122
Marango J, Shimoyama M, Nishio H, Meyer JA, Min DJ, Sirulnik A et al. The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood. 2008 Mar 15;111(6):3145-3154. https://doi.org/10.1182/blood-2007-06-092122
Marango, Jotin ; Shimoyama, Manabu ; Nishio, Hitomi ; Meyer, Julia A. ; Min, Dong Joon ; Sirulnik, Andres ; Martinez-Martinez, Yolanda ; Chesi, Marta ; Bergsagel, Peter Leif ; Zhou, Ming Ming ; Waxman, Samuel ; Leibovitch, Boris A. ; Walsh, Martin J. ; Licht, Jonathan D. / The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. In: Blood. 2008 ; Vol. 111, No. 6. pp. 3145-3154.
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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.",
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