Mutant IDH1 Dysregulates the Differentiation of Mesenchymal Stem Cells in Association with Gene-Specific Histone Modifications to Cartilage- and Bone-Related Genes.
Mutant IDH1 Dysregulates the Differentiation of Mesenchymal Stem Cells in Association with Gene-Specific Histone Modifications to Cartilage- and Bone-Related Genes.
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DOI：
10.1371/journal.pone.0131998
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Toguchida J
中科院分区：
文献类型：
--
作者：
Jin Y;Elalaf H;Watanabe M;Tamaki S;Hineno S;Matsunaga K;Woltjen K;Kobayashi Y;Nagata S;Ikeya M;Kato T Jr;Okamoto T;Matsuda S;Toguchida J
异柠檬酸脱氢酶（IDH）1/2基因的体细胞突变使编码蛋白具有新形态活性，产生潜在的肿瘤代谢物2-羟戊二酸（2-HG），诱导组蛋白和DNA的高甲基化。除中枢神经系统外，软骨肿瘤中IDH1/2突变的发生率在各种类型的肿瘤中是最高的。在良性（软骨瘤）和恶性（软骨肉瘤）类型的软骨肿瘤中都发现了突变，而在其他间质肿瘤（如骨肉瘤）中很少发现突变。为了解决这种独特的肿瘤特异性，我们在此研究了IDH1 R132C对人间充质干细胞（hMSCs）分化特性的影响，这是软骨肿瘤中最普遍的突变体。IDH1 R132C基因诱导MSCs显著增加2-HG的数量，并上调全局组蛋白甲基化。IDH1 R132C的诱导通过增强SOX9和COL2A1基因的表达以及活性标记（H3K4me3）的增加，促进了hMSCs的软骨分化，但破坏了软骨基质的形成。另一方面，IDH1 R132C通过抑制标记（H3K9me3）的增加来抑制ALPL基因的表达，并随后抑制hMSCs和人骨肉瘤细胞的成骨特性。由于成骨特性是骨肉瘤诊断不可或缺的特征，IDH1 R132C对成骨特性的抑制作用可能导致IDH1 R132C突变的骨肉瘤的缺失。这些结果表明，IDH1 R132C通过基因特异性组蛋白调节失调hMSCs的成软骨和成骨分化，从而促进软骨肿瘤的形成。
Somatic mutations in the isocitrate dehydrogenase (IDH)1/2 genes endow encoding proteins with neomorphic activity to produce the potential oncometabolite, 2-hydroxyglutarate (2-HG), which induces the hypermethylation of histones and DNA. The incidence of IDH1/2 mutations in cartilaginous tumors was previously shown to be the highest among various types of tumors, except for those in the central nervous system. Mutations have been detected in both benign (enchondromas) and malignant (chondrosarcomas) types of cartilaginous tumors, whereas they have rarely been found in other mesenchymal tumors such as osteosarcomas. To address this unique tumor specificity, we herein examined the effects of IDH1 R132C, which is the most prevalent mutant in cartilaginous tumors, on the differentiation properties of human mesenchymal stem cells (hMSCs). The induction of the IDH1 R132C gene into MSCs markedly increased the amount of 2-HG and up-regulated global histone methylation. The induction of IDH1 R132C promoted the chondrogenic differentiation of hMSCs by enhancing the expression of SOX9 and COL2A1 genes in association with an increase in the active mark (H3K4me3), but disrupted cartilage matrix formation. On the other hand, IDH1 R132C inhibited expression of the ALPL gene in association with an increase in the repressive mark (H3K9me3), and subsequently inhibited the osteogenic properties of hMSCs and human osteosarcoma cells. Since osteogenic properties are an indispensable feature for the diagnosis of osteosarcoma, the inhibitory effects of IDH1 R132C on osteogenic properties may contribute to the lack of osteosarcomas with the IDH1 R132C mutation. These results suggested that IDH1 R132C contributed to the formation of cartilaginous tumors by dysregulating the chondrogenic and osteogenic differentiation of hMSCs via gene-specific histone modulation.
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影响因子：
11.2
作者：
Abdel-Wahab O;Manshouri T;Patel J;Harris K;Yao J;Hedvat C;Heguy A;Bueso-Ramos C;Kantarjian H;Levine RL;Verstovsek S
通讯作者：
Verstovsek S
影响因子：
64.8
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.
通讯作者：
Thompson, Craig B.
影响因子：
10.5
作者：
Lu C;Venneti S;Akalin A;Fang F;Ward PS;Dematteo RG;Intlekofer AM;Chen C;Ye J;Hameed M;Nafa K;Agaram NP;Cross JR;Khanin R;Mason CE;Healey JH;Lowe SW;Schwartz GK;Melnick A;Thompson CB
通讯作者：
Thompson CB
DOI：
10.1016/j.biocel.2009.10.003
发表时间：
2010-01-01
影响因子：
4
作者：
Furumatsu, Takayuki;Shukunami, Chisa;Ozaki, Toshifumi
通讯作者：
Ozaki, Toshifumi
影响因子：
10.5
作者：
Sasaki, Masato;Knobbe, Christiane B.;Mak, Tak Wah
通讯作者：
Mak, Tak Wah