The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells
The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells
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DOI：
10.1182/blood-2010-07-298349
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发表时间：
2011-01-06
期刊：
影响因子：
20.3
通讯作者：
Licht, Jonathan D.
中科院分区：
文献类型：
--
作者：
Martinez-Garcia, Eva;Popovic, Relja;Licht, Jonathan D.
多发性骨髓瘤 SET 结构域 (MMSET) 蛋白在具有 t(4;14) 易位的多发性骨髓瘤 (MM) 患者中过度表达。尽管研究表明 MMSET/Wolf-Hirschhorn 综合征候选 1 参与了发育，但其在 MM 发病机制中的作用方式在很大程度上尚不清楚。我们发现 MMSET 是 t(4;14) MM 细胞染色质结构和转录的主要调节因子。高水平的 MMSET 与整个基因组中组蛋白 H3 赖氨酸 36 甲基化的增加和赖氨酸 27 甲基化的减少相关，从而导致染色质的结构状态更加开放。 MMSET 表达缺失会改变 MM 细胞的粘附特性、抑制生长并诱导细胞凋亡。因此，受高水平 MMSET 影响的基因与 p53 通路、细胞周期调节和整合素信号传导有关。许多这些基因的调节需要 MMSET 的功能性组蛋白甲基转移酶活性。这些结果表明 MMSET 是 t(4;14)+ MM 中主要的表观遗传调节因子。 （血。2011；117（1）：211-220）
The multiple myeloma SET domain (MMSET) protein is overexpressed in multiple myeloma (MM) patients with the translocation t(4;14). Although studies have shown the involvement of MMSET/Wolf-Hirschhorn syndrome candidate 1 in development, its mode of action in the pathogenesis of MM is largely unknown. We found that MMSET is a major regulator of chromatin structure and transcription in t(4;14) MM cells. High levels of MMSET correlate with an increase in lysine 36 methylation of histone H3 and a decrease in lysine 27 methylation across the genome, leading to a more open structural state of the chromatin. Loss of MMSET expression alters adhesion properties, suppresses growth, and induces apoptosis in MM cells. Consequently, genes affected by high levels of MMSET are implicated in the p53 pathway, cell cycle regulation, and integrin signaling. Regulation of many of these genes required functional histone methyltransferase activity of MMSET. These results implicate MMSET as a major epigenetic regulator in t(4;14)+ MM. (Blood. 2011;117(1):211-220)