The DNA dioxygenase Tet1 regulates H3K27 modification and embryonic stem cell biology independent of its catalytic activity.
The DNA dioxygenase Tet1 regulates H3K27 modification and embryonic stem cell biology independent of its catalytic activity.
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DOI：
10.1093/nar/gkac089
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发表时间：
2022-04-08
影响因子：
14.9
通讯作者：
Dawlaty MM
中科院分区：
文献类型：
--
作者：
Chrysanthou S;Tang Q;Lee J;Taylor SJ;Zhao Y;Steidl U;Zheng D;Dawlaty MM
泰特酶（Tet 1/2/3）氧化5-甲基胞嘧啶以促进DNA去甲基化，并与染色质修饰剂合作以调节基因表达。Tet 1在胚胎干细胞（ESCs）中高度表达，但其在基因调控中的酶和非酶作用尚未解剖。我们已经产生了Tet 1催化失活（Tet 1 m/m）和敲除（Tet 1 −/−）ESC和小鼠来研究这些功能。Tet 1的损失，但不是其催化活性的损失，引起二价（H3 K4 me 3 +; H3 K27 me 3+）发育基因的异常上调，导致分化缺陷。野生型和催化突变体Tet 1占据相似的基因组位点，与H3 K27三甲基转移酶PRC 2和脱乙酰酶复合物Sin 3a在二价基因的启动子处重叠，与解旋酶Chd 4在活性基因处重叠。Tet 1的损失，但不损失其催化活性，削弱富集PRC 2和Sin 3a在二价启动子导致减少H3 K27三甲基化和脱乙酰化，分别在DNA甲基化没有任何变化。Tet 1 −/−，而不是Tet 1 m/m，胚胎表达更高水平的Gata 6，发育迟缓。因此，Tet 1在ESC和早期发育中的关键功能是通过其在调节H3 K27修饰以沉默发育基因中的非催化作用介导的，并且比其在DNA去甲基化中的催化功能更重要。
Tet enzymes (Tet1/2/3) oxidize 5-methylcytosine to promote DNA demethylation and partner with chromatin modifiers to regulate gene expression. Tet1 is highly expressed in embryonic stem cells (ESCs), but its enzymatic and non-enzymatic roles in gene regulation are not dissected. We have generated Tet1 catalytically inactive (Tet1m/m) and knockout (Tet1−/−) ESCs and mice to study these functions. Loss of Tet1, but not loss of its catalytic activity, caused aberrant upregulation of bivalent (H3K4me3+; H3K27me3+) developmental genes, leading to defects in differentiation. Wild-type and catalytic-mutant Tet1 occupied similar genomic loci which overlapped with H3K27 tri-methyltransferase PRC2 and the deacetylase complex Sin3a at promoters of bivalent genes and with the helicase Chd4 at active genes. Loss of Tet1, but not loss of its catalytic activity, impaired enrichment of PRC2 and Sin3a at bivalent promoters leading to reduced H3K27 trimethylation and deacetylation, respectively, in absence of any changes in DNA methylation. Tet1−/−, but not Tet1m/m, embryos expressed higher levels of Gata6 and were developmentally delayed. Thus, the critical functions of Tet1 in ESCs and early development are mediated through its non-catalytic roles in regulating H3K27 modifications to silence developmental genes, and are more important than its catalytic functions in DNA demethylation.
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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
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
12.3
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
通讯作者：
Goodell MA
影响因子：
64.5
作者：
Hanna JH;Saha K;Jaenisch R
通讯作者：
Jaenisch R