OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in development
OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in development
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DOI：
10.7554/elife.34870
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发表时间：
2018-10-16
期刊：
影响因子：
7.7
通讯作者：
Panning, Barbara
中科院分区：
文献类型：
--
作者：
Hrit, Joel;Goodrich, Leeanne;Panning, Barbara
Tet酶将5-甲基胞嘧啶转化为5-羟甲基胞嘧啶和更高级的氧化衍生物。TET稳定地与营养感受酶OGT结合，并被翻译后修饰，这表明代谢和表观基因组之间存在联系。在这里，我们首次展示了OGT的修饰在体外增强了TET1的活性。我们鉴定了一个TET1结构域，它是与OGT结合的必要条件和充分条件，并报告了一个破坏TET1-OGT相互作用的点突变。我们发现这种相互作用是TET1挽救TET突变斑马鱼胚胎中造血干细胞产生所必需的，提示OGT在发育过程中促进了TET1‘S的功能。最后，我们发现，破坏小鼠胚胎干细胞中TET1-OGT的相互作用会改变TET2和5-甲基胞嘧啶的丰度，这伴随着基因表达的变化。这些结果将代谢和表观遗传控制联系在一起，这可能与这两种酶调控的发育和疾病过程有关。
TET enzymes convert 5-methylcytosine to 5-hydroxymethylcytosine and higher oxidized derivatives. TETs stably associate with and are post-translationally modified by the nutrient-sensing enzyme OGT, suggesting a connection between metabolism and the epigenome. Here, we show for the first time that modification by OGT enhances TET1 activity in vitro. We identify a TET1 domain that is necessary and sufficient for binding to OGT and report a point mutation that disrupts the TET1-OGT interaction. We show that this interaction is necessary for TET1 to rescue hematopoetic stem cell production in tet mutant zebrafish embryos, suggesting that OGT promotes TET1's function during development. Finally, we show that disrupting the TET1-OGT interaction in mouse embryonic stem cells changes the abundance of TET2 and 5-methylcytosine, which is accompanied by alterations in gene expression. These results link metabolism and epigenetic control, which may be relevant to the developmental and disease processes regulated by these two enzymes.