IDH mutation impairs histone demethylation and results in a block to cell differentiation.
IDH mutation impairs histone demethylation and results in a block to cell differentiation.
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DOI：
10.1038/nature10860
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发表时间：
2012-02-15
期刊：
影响因子：
64.8
通讯作者：
Thompson, Craig B.
中科院分区：
文献类型：
--
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
异柠檬酸脱氢酶1（IDH 1）和IDH 2的复发性突变已在神经胶质瘤、急性髓性白血病（AML）和软骨肉瘤中发现，并具有从α-酮戊二酸产生2-羟基戊二酸（2 HG）的新酶特性。在这里，我们报告说，2 HG生产IDH突变体可以防止组蛋白去甲基化，这是所需的谱系特异性祖细胞分化成终末分化细胞。在神经胶质瘤患者的肿瘤样本中，IDH突变与神经祖细胞中表达的基因富集的独特基因表达谱相关，这与组蛋白甲基化增加相关。为了测试IDH突变体促进组蛋白甲基化的能力是否有助于阻断非转化细胞中的细胞分化，我们测试了新形态IDH突变体对体外脂肪细胞分化的影响。引入突变体IDH或细胞渗透性2 HG与抑制谱系特异性分化基因的诱导型表达和阻断分化相关。这与抑制性组蛋白甲基化标记的显著增加相关，而启动子DNA甲基化没有观察到变化。神经胶质瘤被发现具有升高水平的类似组蛋白抑制标记。将产生2 HG的突变IDH稳定转染到永生化星形胶质细胞中导致组蛋白甲基化的进行性积累。在检查的标记中，随着细胞在培养物中传代，H3 K9甲基化的增加可重复地先于DNA甲基化的增加。此外，我们发现，在脂肪细胞分化过程中诱导的2 HG-可降解的H3 K9去甲基化酶KDM 4C，和RNA干扰抑制KDM 4C足以阻止分化。总之，这些数据表明，2 HG可以抑制组蛋白去甲基化，并且组蛋白去甲基化的抑制可以足以阻断非转化细胞的分化。
Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.
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影响因子：
50.3
作者：
Xu W;Yang H;Liu Y;Yang Y;Wang P;Kim SH;Ito S;Yang C;Wang P;Xiao MT;Liu LX;Jiang WQ;Liu J;Zhang JY;Wang B;Frye S;Zhang Y;Xu YH;Lei QY;Guan KL;Zhao SM;Xiong Y
通讯作者：
Xiong Y
影响因子：
50.3
作者：
Ward PS;Patel J;Wise DR;Abdel-Wahab O;Bennett BD;Coller HA;Cross JR;Fantin VR;Hedvat CV;Perl AE;Rabinowitz JD;Carroll M;Su SM;Sharp KA;Levine RL;Thompson CB
通讯作者：
Thompson CB
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
10.5
作者：
Esteve, Pierre-Olivier;Chin, Hang Gyeong;Pradhan, Sriharsa
通讯作者：
Pradhan, Sriharsa