Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2.
Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2.
复制标题
DOI：
10.1038/ncomms3166
复制
发表时间：
2013
影响因子：
16.6
通讯作者：
Beck S
中科院分区：
文献类型：
--
作者：
Guilhamon P;Eskandarpour M;Halai D;Wilson GA;Feber A;Teschendorff AE;Gomez V;Hergovich A;Tirabosco R;Fernanda Amary M;Baumhoer D;Jundt G;Ross MT;Flanagan AM;Beck S
异柠檬酸脱氢酶 (IDH) 基因 1 和 2 在急性髓系白血病 (AML)、低级别神经胶质瘤、胆管癌 (CC) 和软骨肉瘤 (CS) 中经常发生突变。对于 AML、低级别神经胶质瘤和 CC，突变 IDH 状态与 DNA 高甲基化表型相关，表明这些癌症的病因学中表观基因组动态发生了改变。在这里，我们发现CS中的IDH变异也与高甲基化表型相关，并显示致癌代谢物2-羟基戊二酸的产生增加，支持突变IDH产生的2-羟基戊二酸作为TET介导的DNA去甲基化抑制剂的作用。对急性髓系白血病、低级别胶质瘤、胆管癌和 CS 甲基化数据的荟萃分析确定了高甲基化靶标中视黄酸受体激活途径中的癌症特异性效应器。通过分析四种癌症类型中高甲基化位点周围的序列基序，并使用染色质免疫沉淀和蛋白质印迹，我们确定了转录因子 EBF1（早期 B 细胞因子 1）作为 TET2 的相互作用伴侣，这表明了调节 DNA 甲基化的序列特异性机制。 与癌症相关的异柠檬酸脱氢酶突变被认为会损害 TET2 依赖性 DNA 去甲基化。通过比较 IDH 突变癌症的甲基化组，作者确定转录因子 EBF1 是 TET2 的伴侣，这提出了一种将 TET2 靶向特定 DNA 序列的可能方法。
Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukaemia (AML), low-grade glioma, cholangiocarcinoma (CC) and chondrosarcoma (CS). For AML, low-grade glioma and CC, mutant IDH status is associated with a DNA hypermethylation phenotype, implicating altered epigenome dynamics in the aetiology of these cancers. Here we show that the IDH variants in CS are also associated with a hypermethylation phenotype and display increased production of the oncometabolite 2-hydroxyglutarate, supporting the role of mutant IDH-produced 2-hydroxyglutarate as an inhibitor of TET-mediated DNA demethylation. Meta-analysis of the acute myeloid leukaemia, low-grade glioma, cholangiocarcinoma and CS methylation data identifies cancer-specific effectors within the retinoic acid receptor activation pathway among the hypermethylated targets. By analysing sequence motifs surrounding hypermethylated sites across the four cancer types, and using chromatin immunoprecipitation and western blotting, we identify the transcription factor EBF1 (early B-cell factor 1) as an interaction partner for TET2, suggesting a sequence-specific mechanism for regulating DNA methylation. Cancer-associated mutations in isocitrate dehydrogenase are proposed to impair TET2-dependent DNA demethylation. By comparing the methylomes of IDH-mutant cancers, the authors identify the transcription factor EBF1 as a partner of TET2, suggesting a possible means for targeting TET2 to specific DNA sequences.
登录
查看更多内容
影响因子：
4.4
作者：
Bibikova, Marina;Barnes, Bret;Shen, Richard
通讯作者：
Shen, Richard
影响因子：
3.7
作者：
Teschendorff AE;Menon U;Gentry-Maharaj A;Ramus SJ;Gayther SA;Apostolidou S;Jones A;Lechner M;Beck S;Jacobs IJ;Widschwendter M
通讯作者：
Widschwendter M
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：
7
作者：
Khulan, Batbayar;Thompson, Reid F.;Greally, John M.
通讯作者：
Greally, John M.
影响因子：
4.2
作者：
Soprano, KJ;Soprano, DR
通讯作者：
Soprano, DR