A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer.
A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer.
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DOI：
10.1093/nar/gkx435
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发表时间：
2017-08-21
影响因子：
14.9
通讯作者：
Issa JJ
中科院分区：
文献类型：
--
作者：
Good CR;Madzo J;Patel B;Maegawa S;Engel N;Jelinek J;Issa JJ
TET1将甲基化的胞嘧啶氧化为5-羟甲基胞嘧啶（5-hydroxymethylcytosine, 5hmC），从而调控DNA甲基化和基因表达。全长TET1 （TET1FL）有一个CXXC结构域，与未甲基化的CpG岛（cgi）结合。这个CXXC结构域允许TET1保护cgi免受异常甲基化，但它也限制了它调节cgi外基因的能力。在这里，我们报道了一种新的TET1 （TET1ALT）异构体，它具有来自内含子2中替代启动子的独特转录起始位点，从而产生具有独特翻译起始位点的蛋白质。重要的是，TET1ALT缺乏CXXC结构域，但保留了催化结构域。TET1ALT在胚胎干细胞中被抑制，但在胚胎和成体组织中被激活，而TET1FL在胚胎干细胞中表达，但在成体组织中被抑制。与TET1FL相比，TET1ALT的过表达显示5hmC的产生对DNA甲基化或基因表达的影响明显（且较弱）。TET1ALT在多种癌症类型中异常激活，包括乳腺癌、子宫癌和胶质母细胞瘤，TET1激活与乳腺癌、子宫癌和卵巢癌的总生存率较低相关。我们的数据表明，癌细胞中主要激活的TET1亚型不能保护CGI甲基化，并可能介导CGI外的动态位点特异性去甲基化。
TET1 oxidizes methylated cytosine into 5-hydroxymethylcytosine (5hmC), resulting in regulation of DNA methylation and gene expression. Full length TET1 (TET1FL) has a CXXC domain that binds to unmethylated CpG islands (CGIs). This CXXC domain allows TET1 to protect CGIs from aberrant methylation, but it also limits its ability to regulate genes outside of CGIs. Here, we report a novel isoform of TET1 (TET1ALT) that has a unique transcription start site from an alternate promoter in intron 2, yielding a protein with a unique translation start site. Importantly, TET1ALT lacks the CXXC domain but retains the catalytic domain. TET1ALT is repressed in embryonic stem cells (ESCs) but becomes activated in embryonic and adult tissues while TET1FL is expressed in ESCs, but repressed in adult tissues. Overexpression of TET1ALT shows production of 5hmC with distinct (and weaker) effects on DNA methylation or gene expression when compared to TET1FL. TET1ALT is aberrantly activated in multiple cancer types including breast, uterine and glioblastoma, and TET1 activation is associated with a worse overall survival in breast, uterine and ovarian cancers. Our data suggest that the predominantly activated isoform of TET1 in cancer cells does not protect from CGI methylation and likely mediates dynamic site-specific demethylation outside of CGIs.
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影响因子：
23.9
作者：
Dawlaty, Meelad M.;Ganz, Kibibi;Powell, Benjamin E.;Hu, Yueh-Chiang;Markoulaki, Styliani;Cheng, Albert W.;Gao, Qing;Kim, Jongpil;Choi, Sang-Woon;Page, David C.;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel