Cooperative Action between SALL4A and TET Proteins in Stepwise Oxidation of 5-Methylcytosine
Cooperative Action between SALL4A and TET Proteins in Stepwise Oxidation of 5-Methylcytosine
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SALL4A 和 TET 蛋白在 5-甲基胞嘧啶逐步氧化中的协同作用。
DOI：
10.1016/j.molcel.2016.10.013
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发表时间：
2016-12-01
期刊：
影响因子：
16
通讯作者：
Zhu, Bing
中科院分区：
文献类型：
--
作者：
Xiong, Jun;Zhang, Zhuqiang;Zhu, Bing
泰特家族酶连续将5-甲基胞嘧啶氧化为5-羟甲基胞嘧啶、5-甲酰基胞嘧啶和5-羧基胞嘧啶，最终导致脱甲基化。5 hmC和泰特酶占据不同的染色质区域，表明在不同的染色质环境中控制5 hmC命运的未知机制。在这里，我们报告说，SALL 4A优先与5 hmC在体外，并占据增强子在小鼠胚胎干细胞在很大程度上TET 1依赖的方式。尽管SALL 4A峰处的大多数5 hmC经历进一步氧化，但在Sall 4基因缺失后，该过程被废除，伴随着这些区域的TET 2的减少。因此，SALL 4A促进5 hmC在其结合位点的进一步氧化，这需要其5 hmC结合活性和TET 2，支持SALL 4A和泰特蛋白在调节增强子处5 mC的逐步氧化中的协同作用。我们的研究将SALL 4A鉴定为5 hmC结合剂，其通过稳定TET 2缔合促进5 hmC氧化，从而微调小鼠胚胎干细胞中发育基因的表达谱。
TET family enzymes successively oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine, leading to eventual demethylation. 5hmC and TET enzymes occupy distinct chromatin regions, suggesting unknown mechanisms controlling the fate of 5hmC within diverse chromatin environments. Here, we report that SALL4A preferentially associates with 5hmC in vitro and occupies enhancers in mouse embryonic stem cells in a largely TET1-dependent manner. Although most 5hmC at SALL4A peaks undergoes further oxidation, this process is abrogated upon deletion of Sall4 gene, with a concomitant reduction of TET2 at these regions. Thus, SALL4A facilitates further oxidation of 5hmC at its binding sites, which requires its 5hmC-binding activity and TET2, supporting a collaborative action between SALL4A and TET proteins in regulating stepwise oxidation of 5mC at enhancers. Our study identifies SALL4A as a 5hmC binder, which facilitates 5hmC oxidation by stabilizing TET2 association, thereby fine-tuning expression profiles of developmental genes in mouse embryonic stem cells.