title: Histone methyltransferase MMSET/NSD2 alters EZH2 binding and reprograms the myeloma epigenome through global and focal changes in H3K36 and H3K27 methylation.
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.
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Relja
authors.initials: R
authors.lastname: Popovic
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Eva
authors.initials: E
authors.lastname: Martinez-Garcia
authors.affiliation: Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, New York, United States of America; Biological Sciences Department, New York City College of Technology, City University of New York, Brooklyn, New York, New York, United States of America.
authors.forename: Eugenia G
authors.initials: EG
authors.lastname: Giannopoulou
authors.affiliation: Department of Statistics, Northwestern University, Evanston, Illinois, United States of America.
authors.forename: Quanwei
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Statistics, Northwestern University, Evanston, Illinois, United States of America.
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ezponda
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Mrinal Y
authors.initials: MY
authors.lastname: Shah
authors.affiliation: Department of Chemistry and Molecular Biosciences, Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois, United States of America.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Will
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Eliza C
authors.initials: EC
authors.lastname: Small
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Youjia
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Marinka
authors.initials: M
authors.lastname: Bulic
authors.affiliation: HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Molecular Biotechnology Center, Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Carrara
authors.affiliation: Molecular Biotechnology Center, Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Raffaele A
authors.initials: RA
authors.lastname: Calogero
authors.affiliation: Department of Engineering Sciences and Applied Mathematics, Northwestern University, Evanston, Illinois, United States of America.
authors.forename: William L
authors.initials: WL
authors.lastname: Kath
authors.affiliation: Department of Chemistry and Molecular Biosciences, Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois, United States of America.
authors.forename: Neil L
authors.initials: NL
authors.lastname: Kelleher
authors.affiliation: Department of Statistics, Northwestern University, Evanston, Illinois, United States of America.
authors.forename: Ji-Ping
authors.initials: JP
authors.lastname: Wang
authors.affiliation: HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Licht
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D002843:Chromatin; D006657:Histones; D034741:RNA, Small Interfering; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D008239:Lysine