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.
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DOI：
10.1371/journal.pgen.1004566
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发表时间：
2014-09
期刊：
影响因子：
4.5
通讯作者：
Licht JD
中科院分区：
文献类型：
--
作者：
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
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骨髓瘤亚型发病机制的驱动因素。MMSET催化组蛋白H3（H3K36me2）上赖氨酸36的二甲基化，并且其过表达导致H3K36me2的整体增加，在整个基因组中以广泛的升高的水平重新分布该标记。在这里，我们证明了MMSET水平的增加也诱导组蛋白H3（H3K27me3）上赖氨酸27三甲基化的整体减少。尽管H3K27甲基化的净减少，但特定的基因组基因座表现出EZH2组蛋白甲基转移酶的增强的募集，并且在该残基上变得高度甲基化。这些效应可能有助于骨髓瘤表型，因为MMSET过表达细胞显示出对EZH2抑制的敏感性增加。此外，我们证明，这种MMSET介导的表观遗传变化需要在蛋白质，包括PHD结构域介导的MMSET招聘染色质内的一些功能域。在体内，通过诱导型shRNA靶向MMSET逆转了组蛋白甲基化变化，并导致无胸腺小鼠中已建立的肿瘤消退。总之，我们的工作阐明了以前未被认识到的MMSET和EZH2之间的相互作用在骨髓瘤肿瘤发生，并确定域时要考虑设计MMSET功能的抑制剂。精确的空间和时间基因表达是正常发育所必需的，并且基因表达的异常调节是包括癌症在内的许多疾病中的常见因素。组蛋白修饰通过改变染色质结构和影响转录调节因子的募集来控制基因表达。在这项研究中，我们证明了两种致癌蛋白MMSET和EZH2之间的相互作用，已知它们分别在赖氨酸36（H3K36）和赖氨酸27（H3K27）上甲基化组蛋白H3。MMSET在骨髓瘤细胞中的过表达增加了H3K36甲基化的总体水平，改变了其在整个基因组中的正常分布，并降低了H3K27甲基化的总体水平。我们发现，虽然大多数基因组在MMSET存在下失去H3K27甲基化，但某些基因座增加了EZH2的募集并增强了H3K27甲基化，导致转录抑制。这些基因的抑制可能在疾病中起重要作用，因为MMSET过表达细胞对靶向EZH2介导的甲基化的小分子抑制剂表现出更高的敏感性。因此，我们的研究表明，特定的局部变化可能超过我们在癌症中经常观察到的总体变化，并暗示EZH2是骨髓瘤细胞中的新治疗靶点。
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. Precise spatial and temporal gene expression is required for normal development, and aberrant regulation of gene expression is a common factor in many diseases, including cancer. Histone modifications contribute to the control of gene expression by altering chromatin structure and affecting the recruitment of transcriptional regulators. In this study, we demonstrate interplay between two oncogenic proteins, MMSET and EZH2, known to methylate histone H3 on lysine 36 (H3K36) and lysine 27 (H3K27), respectively. Overexpression of MMSET in myeloma cells increases global levels of H3K36 methylation, alters its normal distribution throughout the genome and decreases global levels of H3K27 methylation. We found that while the majority of the genome loses H3K27 methylation in the presence of MMSET, certain loci have augmented recruitment of EZH2 and enhanced H3K27 methylation, leading to transcriptional repression. Repression of these genes likely plays an important role in the disease because MMSET-overexpressing cells show higher sensitivity to small molecule inhibitors targeting EZH2-mediated methylation. Thus, our study suggests that the specific local changes may outweigh the gross global changes we frequently observe in cancer and implicates EZH2 as a novel therapeutic target in myeloma cells.
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影响因子：
11.4
作者：
Chng, W-J;Huang, G. F.;Chung, T. H.;Ng, S. B.;Gonzalez-Paz, N.;Troska-Price, T.;Mulligan, G.;Chesi, M.;Bergsagel, P. L.;Fonseca, R.
通讯作者：
Fonseca, R.
影响因子：
16
作者：
Blackledge NP;Zhou JC;Tolstorukov MY;Farcas AM;Park PJ;Klose RJ
通讯作者：
Klose RJ
影响因子：
50.3
作者：
Abdel-Wahab O;Adli M;LaFave LM;Gao J;Hricik T;Shih AH;Pandey S;Patel JP;Chung YR;Koche R;Perna F;Zhao X;Taylor JE;Park CY;Carroll M;Melnick A;Nimer SD;Jaffe JD;Aifantis I;Bernstein BE;Levine RL
通讯作者：
Levine RL
影响因子：
8
作者：
Ezponda, T.;Popovic, R.;Shah, M. Y.;Martinez-Garcia, E.;Zheng, Y.;Min, D-J;Will, C.;Neri, A.;Kelleher, N. L.;Yu, J.;Licht, J. D.
通讯作者：
Licht, J. D.
影响因子：
64.8
作者：
通讯作者：
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