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
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
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.
PLoS Genet. 2014 Sep 4;10(9):e1004566. doi: 10.1371/journal.pgen.1004566. eCollection 2014 Sep.
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.
组蛋白甲基转移酶MMSET在t(4;14)+多发性骨髓瘤患者中的过表达被认为是该亚型骨髓瘤发病机制中的驱动因素。MMSET催化组蛋白H3赖氨酸36的二甲基化（H3K36me2），其过表达导致H3K36me2整体增加，使该标记在全基因组范围内广泛且高水平地重新分布。在此，我们证明MMSET水平升高还会导致组蛋白H3赖氨酸27三甲基化（H3K27me3）整体减少。尽管H3K27甲基化总体减少，但特定基因组位点显示EZH2组蛋白甲基转移酶的募集增强，并在该残基上发生高甲基化。这些效应可能促成了骨髓瘤表型，因为过表达MMSET的细胞对EZH2抑制表现出更高的敏感性。此外，我们证明这种MMSET介导的表观遗传变化需要蛋白质内的多个功能域，包括介导MMSET募集到染色质的PHD结构域。在体内，通过可诱导的短发夹RNA靶向MMSET可逆转组蛋白甲基化变化，并导致无胸腺小鼠中已建立肿瘤的消退。总之，我们的工作阐明了MMSET和EZH2在骨髓瘤发生过程中以前未被认识的相互作用，并确定了设计MMSET功能抑制剂时应考虑的结构域。
