TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma.
TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma.
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DOI：
10.1016/j.celrep.2014.04.040
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发表时间：
2014-06-12
期刊：
影响因子：
8.8
通讯作者：
Godley LA
中科院分区：
文献类型：
--
作者：
Mariani CJ;Vasanthakumar A;Madzo J;Yesilkanal A;Bhagat T;Yu Y;Bhattacharyya S;Wenger RH;Cohn SL;Nanduri J;Verma A;Prabhakar NR;Godley LA
10 - 11易位5-甲基胞嘧啶双加氧酶（泰特）家族催化5-甲基胞嘧啶（5-mC）转化为5-羟甲基胞嘧啶（5-hmC），5-hmC是促进基因表达的修饰的胞嘧啶碱基。细胞通过诱导转录程序对缺氧作出反应，该转录程序部分受氧依赖性双加氧酶调节，需要Fe（II）和α-酮戊二酸。考虑到泰特酶也需要这些辅因子，我们假设TET调节缺氧诱导的转录程序。在这里，我们表明，缺氧增加全球5-hmC水平，5-hmC密度在典型的缺氧反应基因的积累。5-hmC增益的一个子集与缺氧反应元件共定位，促进DNA去甲基化和HIF结合。缺氧导致TET 1的转录激活，并且缺氧应答基因的完全诱导和全局5-hmC增加需要TET 1。最后，我们表明，5-hmC的增加和TET 1在缺氧上调HIF-1依赖。这些发现建立TET 1介导的5-hmC的变化作为一个重要的表观遗传组成部分的缺氧反应。
The ten-eleven-translocation 5-methylcytosine dioxygenase (TET) family of enzymes catalyzes the conversion of 5-methylcytosine (5-mC) to 5-hydroxyme-thylcytosine (5-hmC), a modified cytosine base that facilitates gene expression. Cells respond to hypoxia by inducing a transcriptional program regulated in part by oxygen-dependent dioxygenases that require Fe(II) and α-ketoglutarate. Given that the TET enzymes also require these cofactors, we hypothesized that the TETs regulate the hypoxia-induced transcriptional program. Here, we demonstrate that hypoxia increases global 5-hmC levels, with accumulation of 5-hmC density at canonical hypoxia response genes. A subset of 5-hmC gains colocalize with hypoxia response elements facilitating DNA demethylation and HIF binding. Hypoxia results in transcriptional activation of TET1, and full induction of hypoxia-responsive genes and global 5-hmC increases require TET1. Finally, we show that 5-hmC increases and TET1 upregulation in hypoxia are HIF-1 dependent. These findings establish TET1-mediated 5-hmC changes as an important epigenetic component of the hypoxic response.