Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation

Relja Popovic, Eva Martinez-Garcia, Eugenia G. Giannopoulou, Quanwei Zhang, Qingyang Zhang, Teresa Ezponda, Mrinal Y. Shah, Yupeng Zheng, Christine M. Will, Eliza C. Small, Youjia Hua, Marinka Bulic, Yanwen Jiang, Matteo Carrara, Raffaele A. Calogero, William L. Kath, Neil L. Kelleher, Ji Ping Wang, Olivier Elemento, Jonathan D. Licht

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Overexpression of the histone methyltransferase MMSET in t(4;14)+ multiple myeloma patients is believed to be the driving factor in the pathogenesis of this subtype of myeloma. MMSET catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2), and its overexpression causes a global increase in H3K36me2, redistributing this mark in a broad, elevated level across the genome. Here, we demonstrate that an increased level of MMSET also induces a global reduction of lysine 27 trimethylation on histone H3 (H3K27me3). Despite the net decrease in H3K27 methylation, specific genomic loci exhibit enhanced recruitment of the EZH2 histone methyltransferase and become hypermethylated on this residue. These effects likely contribute to the myeloma phenotype since MMSET-overexpressing cells displayed increased sensitivity to EZH2 inhibition. Furthermore, we demonstrate that such MMSET-mediated epigenetic changes require a number of functional domains within the protein, including PHD domains that mediate MMSET recruitment to chromatin. In vivo, targeting of MMSET by an inducible shRNA reversed histone methylation changes and led to regression of established tumors in athymic mice. Together, our work elucidates previously unrecognized interplay between MMSET and EZH2 in myeloma oncogenesis and identifies domains to be considered when designing inhibitors of MMSET function.

Original languageEnglish (US)
JournalPLoS Genetics
Volume10
Issue number9
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

myeloma
methyltransferases
methylation
histones
Histones
Methylation
Lysine
tumor
targeting
phenotype
inhibitor
genomics
genome
Multiple Myeloma
lysine
Epigenomics
Nude Mice
Small Interfering RNA
Chromatin
protein

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation. / Popovic, Relja; Martinez-Garcia, Eva; Giannopoulou, Eugenia G.; Zhang, Quanwei; Zhang, Qingyang; Ezponda, Teresa; Shah, Mrinal Y.; Zheng, Yupeng; Will, Christine M.; Small, Eliza C.; Hua, Youjia; Bulic, Marinka; Jiang, Yanwen; Carrara, Matteo; Calogero, Raffaele A.; Kath, William L.; Kelleher, Neil L.; Wang, Ji Ping; Elemento, Olivier; Licht, Jonathan D.

In: PLoS Genetics, Vol. 10, No. 9, 01.01.2014.

Research output: Contribution to journalArticle

Popovic, R, Martinez-Garcia, E, Giannopoulou, EG, Zhang, Q, Zhang, Q, Ezponda, T, Shah, MY, Zheng, Y, Will, CM, Small, EC, Hua, Y, Bulic, M, Jiang, Y, Carrara, M, Calogero, RA, Kath, WL, Kelleher, NL, Wang, JP, Elemento, O & Licht, JD 2014, 'Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation', PLoS Genetics, vol. 10, no. 9. https://doi.org/10.1371/journal.pgen.1004566
Popovic, Relja ; Martinez-Garcia, Eva ; Giannopoulou, Eugenia G. ; Zhang, Quanwei ; Zhang, Qingyang ; Ezponda, Teresa ; Shah, Mrinal Y. ; Zheng, Yupeng ; Will, Christine M. ; Small, Eliza C. ; Hua, Youjia ; Bulic, Marinka ; Jiang, Yanwen ; Carrara, Matteo ; Calogero, Raffaele A. ; Kath, William L. ; Kelleher, Neil L. ; Wang, Ji Ping ; Elemento, Olivier ; Licht, Jonathan D. / Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation. In: PLoS Genetics. 2014 ; Vol. 10, No. 9.
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abstract = "Overexpression of the histone methyltransferase MMSET in t(4;14)+ multiple myeloma patients is believed to be the driving factor in the pathogenesis of this subtype of myeloma. MMSET catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2), and its overexpression causes a global increase in H3K36me2, redistributing this mark in a broad, elevated level across the genome. Here, we demonstrate that an increased level of MMSET also induces a global reduction of lysine 27 trimethylation on histone H3 (H3K27me3). Despite the net decrease in H3K27 methylation, specific genomic loci exhibit enhanced recruitment of the EZH2 histone methyltransferase and become hypermethylated on this residue. These effects likely contribute to the myeloma phenotype since MMSET-overexpressing cells displayed increased sensitivity to EZH2 inhibition. Furthermore, we demonstrate that such MMSET-mediated epigenetic changes require a number of functional domains within the protein, including PHD domains that mediate MMSET recruitment to chromatin. In vivo, targeting of MMSET by an inducible shRNA reversed histone methylation changes and led to regression of established tumors in athymic mice. Together, our work elucidates previously unrecognized interplay between MMSET and EZH2 in myeloma oncogenesis and identifies domains to be considered when designing inhibitors of MMSET function.",
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T1 - Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation

AU - Popovic, Relja

AU - Martinez-Garcia, Eva

AU - Giannopoulou, Eugenia G.

AU - Zhang, Quanwei

AU - Zhang, Qingyang

AU - Ezponda, Teresa

AU - Shah, Mrinal Y.

AU - Zheng, Yupeng

AU - Will, Christine M.

AU - Small, Eliza C.

AU - Hua, Youjia

AU - Bulic, Marinka

AU - Jiang, Yanwen

AU - Carrara, Matteo

AU - Calogero, Raffaele A.

AU - Kath, William L.

AU - Kelleher, Neil L.

AU - Wang, Ji Ping

AU - Elemento, Olivier

AU - Licht, Jonathan D.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Overexpression of the histone methyltransferase MMSET in t(4;14)+ multiple myeloma patients is believed to be the driving factor in the pathogenesis of this subtype of myeloma. MMSET catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2), and its overexpression causes a global increase in H3K36me2, redistributing this mark in a broad, elevated level across the genome. Here, we demonstrate that an increased level of MMSET also induces a global reduction of lysine 27 trimethylation on histone H3 (H3K27me3). Despite the net decrease in H3K27 methylation, specific genomic loci exhibit enhanced recruitment of the EZH2 histone methyltransferase and become hypermethylated on this residue. These effects likely contribute to the myeloma phenotype since MMSET-overexpressing cells displayed increased sensitivity to EZH2 inhibition. Furthermore, we demonstrate that such MMSET-mediated epigenetic changes require a number of functional domains within the protein, including PHD domains that mediate MMSET recruitment to chromatin. In vivo, targeting of MMSET by an inducible shRNA reversed histone methylation changes and led to regression of established tumors in athymic mice. Together, our work elucidates previously unrecognized interplay between MMSET and EZH2 in myeloma oncogenesis and identifies domains to be considered when designing inhibitors of MMSET function.

AB - Overexpression of the histone methyltransferase MMSET in t(4;14)+ multiple myeloma patients is believed to be the driving factor in the pathogenesis of this subtype of myeloma. MMSET catalyzes dimethylation of lysine 36 on histone H3 (H3K36me2), and its overexpression causes a global increase in H3K36me2, redistributing this mark in a broad, elevated level across the genome. Here, we demonstrate that an increased level of MMSET also induces a global reduction of lysine 27 trimethylation on histone H3 (H3K27me3). Despite the net decrease in H3K27 methylation, specific genomic loci exhibit enhanced recruitment of the EZH2 histone methyltransferase and become hypermethylated on this residue. These effects likely contribute to the myeloma phenotype since MMSET-overexpressing cells displayed increased sensitivity to EZH2 inhibition. Furthermore, we demonstrate that such MMSET-mediated epigenetic changes require a number of functional domains within the protein, including PHD domains that mediate MMSET recruitment to chromatin. In vivo, targeting of MMSET by an inducible shRNA reversed histone methylation changes and led to regression of established tumors in athymic mice. Together, our work elucidates previously unrecognized interplay between MMSET and EZH2 in myeloma oncogenesis and identifies domains to be considered when designing inhibitors of MMSET function.

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