Tet1 Suppresses p21 to Ensure Proper Cell Cycle Progression in Embryonic Stem Cells.
Tet1 Suppresses p21 to Ensure Proper Cell Cycle Progression in Embryonic Stem Cells.
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DOI：
10.3390/cells11081366
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发表时间：
2022-04-17
期刊：
影响因子：
6
通讯作者：
Dawlaty, Meelad M.
中科院分区：
文献类型：
--
作者：
Chrysanthou, Stephanie;Flores, Julio C.;Dawlaty, Meelad M.
10 - 11易位1 （Tet1）是一种DNA双加氧酶，通过氧化5-甲基胞嘧啶促进DNA去甲基化。它还可以与染色质激活和抑制复合物合作，以调节独立于其酶活性的基因表达。Tet1在胚胎干细胞（ESCs）中高度表达，并调节多能性和分化。然而，其在ESC细胞周期进程和增殖中的作用尚未被研究。通过一系列Tet1催化突变体（Tet1m/m）、敲除（Tet1−/−）和野生型（Tet1+/+）小鼠ESCs (mESCs)，我们发现Tet1在mESCs的正常细胞周期进程和增殖中具有非催化作用。Tet1−/−，而不是Tet1m/m， mESCs在G1期间表现出显著的增殖减少和延迟进展。我们发现细胞周期蛋白依赖性激酶抑制剂p21/Cdkn1a在Tet1−/−mESCs中唯一上调，其下调纠正了缓慢的增殖和延迟的G1进展。在机制上，我们发现p21是Tet1的直接靶点。p21启动子上的Tet1占用与抑制性组蛋白标记H3K27me3以及H3K27三甲基转移酶PRC2组分Ezh2重叠。Tet1的缺失，而不是其催化活性的缺失，显著降低了p21启动子上Ezh2和H3K27三甲基化的富集，而不影响DNA甲基化水平。我们还发现Tet1−/−mESCs的增殖缺陷与其分化缺陷无关。总之，这些发现确定了Tet1在mESCs中抑制p21的非催化作用，以确保g1到s的快速进展，这是ESC增殖的关键标志。该研究还证实了Tet1除了在ESC多能性和分化中发挥作用外，还是ESC增殖的表观遗传调节剂。
Ten eleven translocation 1 (Tet1) is a DNA dioxygenase that promotes DNA demethylation by oxidizing 5-methylcytosine. It can also partner with chromatin-activating and repressive complexes to regulate gene expressions independent of its enzymatic activity. Tet1 is highly expressed in embryonic stem cells (ESCs) and regulates pluripotency and differentiation. However, its roles in ESC cell cycle progression and proliferation have not been investigated. Using a series of Tet1 catalytic mutant (Tet1m/m), knockout (Tet1−/−) and wild type (Tet1+/+) mouse ESCs (mESCs), we identified a non-catalytic role of Tet1 in the proper cell cycle progression and proliferation of mESCs. Tet1−/−, but not Tet1m/m, mESCs exhibited a significant reduction in proliferation and delayed progression through G1. We found that the cyclin-dependent kinase inhibitor p21/Cdkn1a was uniquely upregulated in Tet1−/− mESCs and its knockdown corrected the slow proliferation and delayed G1 progression. Mechanistically, we found that p21 was a direct target of Tet1. Tet1 occupancy at the p21 promoter overlapped with the repressive histone mark H3K27me3 as well as with the H3K27 trimethyl transferase PRC2 component Ezh2. A loss of Tet1, but not loss of its catalytic activity, significantly reduced the enrichment of Ezh2 and H3K27 trimethylation at the p21 promoter without affecting the DNA methylation levels. We also found that the proliferation defects of Tet1−/− mESCs were independent of their differentiation defects. Together, these findings established a non-catalytic role for Tet1 in suppressing p21 in mESCs to ensure a rapid G1-to-S progression, which is a key hallmark of ESC proliferation. It also established Tet1 as an epigenetic regulator of ESC proliferation in addition to its previously defined roles in ESC pluripotency and differentiation.
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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
影响因子：
13.6
作者：
Ma L;Tang Q;Gao X;Lee J;Lei R;Suzuki M;Zheng D;Ito K;Frenette PS;Dawlaty MM
通讯作者：
Dawlaty MM
影响因子：
11.2
作者：
Filipczak, Piotr T.;Leng, Shuguang;Belinsky, Steven A.
通讯作者：
Belinsky, Steven A.
G1/S 相变期间 Rb 磷酸化需要 Tet1
DOI：
10.1016/j.bbrc.2013.02.110
发表时间：
2013-05-03
影响因子：
3.1
作者：
Huang, Shengsong;Zhu, Ziqi;Wu, Denglong
通讯作者：
Wu, Denglong
DOI：
10.1126/science.1170116
发表时间：
2009-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Tahiliani M;Koh KP;Shen Y;Pastor WA;Bandukwala H;Brudno Y;Agarwal S;Iyer LM;Liu DR;Aravind L;Rao A
通讯作者：
Rao A