TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions.
TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions.
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DOI：
10.1016/j.celrep.2021.108776
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发表时间：
2021-02-23
期刊：
影响因子：
8.8
通讯作者：
Carroll JS
中科院分区：
文献类型：
--
作者：
Broome R;Chernukhin I;Jamieson S;Kishore K;Papachristou EK;Mao SQ;Tejedo CG;Mahtey A;Theodorou V;Groen AJ;D'Santos C;Balasubramanian S;Farcas AM;Siersbæk R;Carroll JS
雌激素受体-受体(ER-α，ER)推动ER阳性(ER+)乳腺癌的发展。转录因子GATA3与内质网功能密切相关，但其在这一过程中的确切作用尚不清楚。定量蛋白质组学被用来评估内质网复合体在GATA3耗尽后的变化。出乎意料的是，在没有GATA3的情况下，内质网复合体中几乎没有蛋白质丢失，唯一的主要变化是双加氧酶TET2的耗尽。在多种乳腺癌模型中，TET2结合构成了ER结合的一个几乎全部的子集，TET2的丢失与增殖途径的激活减少有关。TET2基因敲除似乎没有改变全球甲基化胞嘧啶(5mC)的水平；然而，5mC到5-羟甲基胞嘧啶(5hmC)的氧化显著减少，这些事件发生在ER增强子上。这些发现表明TET2参与了ER位点5hmC的维持，为TET2介导的ER靶基因调控提供了一种潜在的机制。在多个乳腺癌模型中，TET2通过缺失GATA3TET2全球染色质结合追踪ER/GATA3的染色质结合被鉴定为ER复合体的组成部分。TET2的丢失与ER靶基因的表达失调有关。TET2在ER位点同时丢失5hmC为深入了解TET2的S在ER活性中的作用提供了见解。利用定量蛋白质组学和染色质免疫沉淀技术探讨TET2对ER/GATA3转录活性的影响。TET2跟踪乳腺癌模型中ER染色质的结合，并在ER增强子维持5-羟甲基胞嘧啶方面发挥重要作用，揭示了TET2在ER驱动的基因表达中的作用。
Estrogen receptor-α (ER) drives tumor development in ER-positive (ER+) breast cancer. The transcription factor GATA3 has been closely linked to ER function, but its precise role in this setting remains unclear. Quantitative proteomics was used to assess changes to the ER complex in response to GATA3 depletion. Unexpectedly, few proteins were lost from the ER complex in the absence of GATA3, with the only major change being depletion of the dioxygenase TET2. TET2 binding constituted a near-total subset of ER binding in multiple breast cancer models, with loss of TET2 associated with reduced activation of proliferative pathways. TET2 knockdown did not appear to change global methylated cytosine (5mC) levels; however, oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) was significantly reduced, and these events occurred at ER enhancers. These findings implicate TET2 in the maintenance of 5hmC at ER sites, providing a potential mechanism for TET2-mediated regulation of ER target genes. TET2 is identified as a component of the ER complex through depletion of GATA3 TET2 global chromatin binding tracks that of ER/GATA3 in multiple breast cancer models Loss of TET2 is linked to dysregulated expression of ER target genes Concurrent loss of 5hmC at ER sites provides insights into TET2’s role in ER activity Broome et al. use quantitative proteomics and chromatin immunoprecipitation to explore the contribution of TET2 to ER/GATA3 transcriptional activity. TET2 tracks ER chromatin binding in breast cancer models and plays an essential role in the maintenance of 5-hydroxymethylcytosine at ER enhancers, revealing a role for TET2 in ER-driven gene expression.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
64.5
作者：
Hah N;Danko CG;Core L;Waterfall JJ;Siepel A;Lis JT;Kraus WL
通讯作者：
Kraus WL
影响因子：
30.8
作者：
Carroll, Jason S.;Meyer, Clifford A.;Brown, Myles
通讯作者：
Brown, Myles
影响因子：
12.3
作者：
Akalin A;Kormaksson M;Li S;Garrett-Bakelman FE;Figueroa ME;Melnick A;Mason CE
通讯作者：
Mason CE
影响因子：
8.8
作者：
Jin SG;Zhang ZM;Dunwell TL;Harter MR;Wu X;Johnson J;Li Z;Liu J;Szabó PE;Lu Q;Xu GL;Song J;Pfeifer GP
通讯作者：
Pfeifer GP