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

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Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome Through Global and Focal Changes in H3K36 and H3K27 Methylation Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation Relja Popovic1., Eva Martinez-Garcia1., Eugenia G. Giannopoulou2,3, Quanwei Zhang4, Qingyang Zhang4, Teresa Ezponda1, Mrinal Y. Shah1, Yupeng Zheng5, Christine M. Will1, Eliza C. Small1, Youjia Hua1, Marinka Bulic1, Yanwen Jiang6, Matteo Carrara7, Raffaele A. Calogero7, William L. Kath8, Neil L. Kelleher5, Ji-Ping Wang4, Olivier Elemento6, Jonathan D. Licht1* 1 Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America, 2 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, 3 Biological Sciences Department, New York City College of Technology, City University of New York, Brooklyn, New York, New York, United States of America, 4 Department of Statistics, Northwestern University, Evanston, Illinois, United States of America, 5 Department of Chemistry and Molecular Biosciences, Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois, United States of America, 6 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, 7 Molecular Biotechnology Center, Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy, 8 Department of Engineering Sciences and Applied Mathematics, Northwestern University, Evanston, Illinois, United States of America 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. Citation: Popovic R, Martinez-Garcia E, Giannopoulou EG, Zhang Q, Zhang Q, et al. (2014) Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation. PLoS Genet 10(9): e1004566. doi:10.1371/journal. pgen.1004566 Editor: Tom Milne, Oxford University, United Kingdom Received November 8, 2013; Accepted June 30, 2014; Published September 4, 2014 Copyright: ß 2014 Popovic et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: JDL, QuZ, WLK, NLK and JPW are supported by National Cancer Institute Physical Sciences in Oncology Center program (U54CA143869). JDL is supported by National Institutes of Health grant (RO1CA12320). OE and JDL are supported by Leukemia and Lymphoma Society Specialized Center of Research Excellence awards (7132-08 and 7006-13). NLK is supported by National Institute of General Medical Sciences grant (RO1GM067193). RP is supported by Multiple Myeloma Research Foundation Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: [email protected] . These authors contributed equally to this work. Introduction methyltransferases (HMTs), are a recurrent theme in the pathogenesis of malignancy. Recently, HMTs have attracted Epigenetic control of gene expression plays a critical role in particular interest due to their potential as therapeutic targets [1], many biological processes and aberrant chromatin regulation is but our understanding of the mechanisms by which abnormal the driving factor in a multitude of diseases, including cancer. histone methylation leads to disease development is still incom- Through studies of chromosomal rearrangements, copy number plete. changes, and more recently, sequencing of cancer genomes, it has The specificity of each HMT is encoded within the catalytic become apparent that genetic alterations of enzymes responsible SET (Suppressor of variegation, Enhancer of zeste and Trithorax) for covalent modification of histones or DNA, including histone domain. For example, trimethylation of lysine 27 on histone H3 PLOS Genetics | www.plosgenetics.org 1 September 2014 | Volume 10 | Issue 9 | e1004566 MMSET Reprograms Myeloma Epigenome Author Summary MMSET overexpression in cancer are beginning to be elucidated. We and others showed that downregulation of MMSET Precise spatial and temporal gene expression is required expression in t(4;14)+ cell lines leads to decreased proliferation for normal development, and aberrant regulation of gene and loss of clonogenic potential [12,26]. In myeloma and prostate expression is a common factor in many diseases, including cells, overexpression of MMSET causes a dramatic global increase cancer. Histone modifications contribute to the control of in H3K36me2, accompanied with a concomitant genome-wide gene expression by altering chromatin structure and loss of H3K27me3 [12,20,27]. The change in histone methylation affecting the recruitment of transcriptional regulators. In is dependent on the HMT activity of MMSET and leads to altered this study, we demonstrate interplay between two chromatin structure and aberrant gene expression [12]. oncogenic proteins, MMSET and EZH2, known to methyl- In this work, we aimed to elucidate the mechanisms by which ate histone H3 on lysine 36 (H3K36) and lysine 27 (H3K27), MMSET alters gene expression in MM. Genome-wide chromatin respectively. Overexpression of MMSET in myeloma cells increases global levels of H3K36 methylation, alters its analysis showed that MMSET overexpression led to a widespread normal distribution throughout the genome and decreas- redistribution in H3K36me2 across promoters, gene bodies and es global levels of H3K27 methylation. We found that while intergenic regions, and gene activation correlated with removal of the majority of the genome loses H3K27 methylation in the inhibitory H3K27me3 chromatin mark. Surprisingly, overex- the presence of MMSET, certain loci have augmented pression of MMSET induced transcriptional repression at specific recruitment of EZH2 and enhanced H3K27 methylation, loci that became highly enriched for EZH2 and H3K27me3. This leading to transcriptional repression. Repression of these increase was associated with augmented sensitivity to small genes likely plays an important role in the disease because molecule inhibitors targeting EZH2 methyltransferase activity. MMSET-overexpressing cells show higher sensitivity to The ability of an epigenetic regulator to modify histones or DNA small molecule inhibitors targeting EZH2-mediated meth- depends on its ability to target specific loci through direct ylation. Thus, our study suggests that the specific local interaction with chromatin, or through recruitment by other changes may outweigh the gross global changes we transcriptional cofactors. We identified the domains of MMSET frequently observe in cancer and implicates EZH2 as a that are required for its recruitment to chromatin and that are novel therapeutic target in myeloma cells. necessary for methylation of H3K36 and loss of H3K27 methylation in t(4;14)+ cells. Both of these functions are necessary for the oncogenic potential of MMSET. Lastly, we validated MMSET as a therapeutic target by showing that loss of MMSET (H3K27me3) is mediated by the EZH2 protein, a member of the expression in established t(4;14)+ tumors led to a decrease in Polycomb Repressive Complex 2 (PRC2) [2]. Binding of EZH2 tumor burden and an increase in survival. Together, our results and the presence of the H3K27me3 mark are found at reveal an interplay between H3K36 and H3K27 methylation in transcriptionally repressed loci and have been shown to play a t(4;14)+ myeloma and identify the domains of MMSET that could role in recruitment of additional transcriptional repressors, be targeted in efforts to improve outcomes of this currently including DNA methyltransferases (DNMTs) [3,4]. EZH2 gain- incurable disease. of-function mutations that enhance H3K27me3 levels are pathogenic for germinal center type large B cell lymphomas Results [5,6], whereas global loss of EZH2 function due to mutation/ deletion
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