DNMT3A and TET1 cooperate to regulate promoter epigenetic landscapes in mouse embryonic stem cells.
DNMT3A and TET1 cooperate to regulate promoter epigenetic landscapes in mouse embryonic stem cells.
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DOI：
10.1186/s13059-018-1464-7
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发表时间：
2018-07-12
期刊：
影响因子：
12.3
通讯作者：
Goodell MA
中科院分区：
文献类型：
--
作者：
Gu T;Lin X;Cullen SM;Luo M;Jeong M;Estecio M;Shen J;Hardikar S;Sun D;Su J;Rux D;Guzman A;Lee M;Qi LS;Chen JJ;Kyba M;Huang Y;Chen T;Li W;Goodell MA
DNA甲基化是一种可遗传的表观遗传标记，能够稳定但可逆地抑制基因。在哺乳动物细胞中，DNA甲基转移酶(DNMT)负责将胞嘧啶修饰为5-甲基胞嘧啶(5mC)，后者可被Tet双加氧酶进一步氧化，最终导致DNA去甲基化。然而，这两个蛋白质家族的全基因组合作和功能，特别是在被称为峡谷的大型甲基化区域，仍然很大程度上是未知的。在这里，我们证明了DNMT3A和TET1在小鼠胚胎干细胞中以互补和竞争的方式发挥作用，介导适当的表观遗传景观和基因表达。较长的DNMT3A亚型DNMT3A1在远端启动子和峡谷边缘表现出显著的富集性，但在TET1结合突出的近端启动子和峡谷中被排除在外。Tet1的缺失增加了与野生型TET1结合的基因及其周围的DNMT3A1结合能力。然而，DNMT3A的缺失对TET1与染色质的结合影响不大，这表明TET1可能通过保护其靶标不受DNMT3A的影响和为DNA甲基化建立边界来部分限制DNA甲基化。局部CpG密度可能决定它们的互补结合模式，因此甲基化情况在DNA序列中编码。此外，DNMT3A和TET1影响组蛋白修饰，进而调节基因表达。特别是，它们调节多梳抑制复合体2(PRC2)介导的H3K27me3浓缩，以限制二价启动子的基因表达。我们认为，DNMT3A和TET1通过功能上的相互作用调节表观基因组和基因在特定靶点的表达。本文的在线版本(10.1186/s13059-0181464-7)包含补充材料，可供授权用户使用。
DNA methylation is a heritable epigenetic mark, enabling stable but reversible gene repression. In mammalian cells, DNA methyltransferases (DNMTs) are responsible for modifying cytosine to 5-methylcytosine (5mC), which can be further oxidized by the TET dioxygenases to ultimately cause DNA demethylation. However, the genome-wide cooperation and functions of these two families of proteins, especially at large under-methylated regions, called canyons, remain largely unknown. Here we demonstrate that DNMT3A and TET1 function in a complementary and competitive manner in mouse embryonic stem cells to mediate proper epigenetic landscapes and gene expression. The longer isoform of DNMT3A, DNMT3A1, exhibits significant enrichment at distal promoters and canyon edges, but is excluded from proximal promoters and canyons where TET1 shows prominent binding. Deletion of Tet1 increases DNMT3A1 binding capacity at and around genes with wild-type TET1 binding. However, deletion of Dnmt3a has a minor effect on TET1 binding on chromatin, indicating that TET1 may limit DNA methylation partially by protecting its targets from DNMT3A and establishing boundaries for DNA methylation. Local CpG density may determine their complementary binding patterns and therefore that the methylation landscape is encoded in the DNA sequence. Furthermore, DNMT3A and TET1 impact histone modifications which in turn regulate gene expression. In particular, they regulate Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 enrichment to constrain gene expression from bivalent promoters. We conclude that DNMT3A and TET1 regulate the epigenome and gene expression at specific targets via their functional interplay. The online version of this article (10.1186/s13059-018-1464-7) contains supplementary material, which is available to authorized users.
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影响因子：
23.9
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影响因子：
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