The transcription factor TFCP2L1 induces expression of distinct target genes and promotes self-renewal of mouse and human embryonic stem cells
The transcription factor TFCP2L1 induces expression of distinct target genes and promotes self-renewal of mouse and human embryonic stem cells
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转录因子 TFCP2L1 诱导不同靶基因的表达并促进小鼠和人类胚胎干细胞的自我更新
DOI：
10.1074/jbc.ra118.006341
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发表时间：
2019-02
影响因子：
4.8
通讯作者：
Ye Shou Dong
中科院分区：
文献类型：
--
作者：
Wang Xiaohu;Wang Xiaoxiao;Zhang Shuyuan;Sun Hongwei;Li Sijia;Ding Huiwen;You Yu;Zhang Xuewu;Ye Shou Dong
TFCP2L1（转录因子CP2样1）是一种转录调节因子，对维持小鼠和人胚胎干细胞（ESC）多能性至关重要。然而，直接的TFCP2L1靶基因是未表征的。在这里，使用基因过表达，免疫印迹，定量实时PCR，ChIP和报告基因测定，我们表明，TFCP2L1主要诱导雌激素相关受体β（Esrrb）的表达，支持小鼠ESC的身份，也选择性地增强Kruppel样因子4（Klf4）的表达，从而促进人类ESC自我更新。具体来说，我们发现，在小鼠胚胎干细胞，TFCP2L1直接结合到Esrrb基因启动子，并调节其转录。Esrrb基因敲低削弱了Tfcp2l1诱导白细胞介素6家族细胞因子（白血病抑制因子）非依赖性ESC自我更新和将外胚层干细胞重编程为幼稚多能性的能力。相反，Esrrb过表达阻断了Tfcp2l1下调诱导的分化。此外，我们将Klf4鉴定为人ESC中的直接TFCP2L1靶点，绕过了短期人ESC自我更新中对激活素A和碱性成纤维细胞生长因子的需求。强化Klf4表达概括了Tfcp2l1的自我更新促进作用，而Klf4敲除消除了这些作用并导致集落形成能力丧失。这些发现表明，TFCP2L1在幼稚和引发的多能性中具有不同的功能，这些见解可能有助于阐明多能性的不同状态。
TFCP2L1 (transcription factor CP2-like 1) is a transcriptional regulator critical for maintaining mouse and human embryonic stem cell (ESC) pluripotency. However, the direct TFCP2L1 target genes are uncharacterized. Here, using gene overexpression, immunoblotting, quantitative real-time PCR, ChIP, and reporter gene assays, we show that TFCP2L1 primarily induces estrogen-related receptor β (Esrrb) expression that supports mouse ESC identity and also selectively enhances Kruppel-like factor 4 (Klf4) expression and thereby promotes human ESC self-renewal. Specifically, we found that in mouse ESCs, TFCP2L1 binds directly to the Esrrb gene promoter and regulates its transcription. Esrrb knockdown impaired Tfcp2l1's ability to induce interleukin 6 family cytokine (leukemia inhibitory factor)–independent ESC self-renewal and to reprogram epiblast stem cells to naïve pluripotency. Conversely, Esrrb overexpression blocked differentiation induced by Tfcp2l1 down-regulation. Moreover, we identified Klf4 as a direct TFCP2L1 target in human ESCs, bypassing the requirement for activin A and basic fibroblast growth factor in short-term human ESC self-renewal. Enforced Klf4 expression recapitulated the self-renewal–promoting effect of Tfcp2l1, whereas Klf4 knockdown eliminated these effects and caused loss of colony-forming capability. These findings indicate that TFCP2L1 functions differently in naïve and primed pluripotency, insights that may help elucidate the different states of pluripotency.
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影响因子：
5.9
作者：
Guo G;von Meyenn F;Santos F;Chen Y;Reik W;Bertone P;Smith A;Nichols J
通讯作者：
Nichols J
影响因子：
64.5
作者：
Takashima Y;Guo G;Loos R;Nichols J;Ficz G;Krueger F;Oxley D;Santos F;Clarke J;Mansfield W;Reik W;Bertone P;Smith A
通讯作者：
Smith A
影响因子：
23.9
作者：
Martello, Graziano;Sugimoto, Toshimi;Diamanti, Evangelia;Joshi, Anagha;Hannah, Rebecca;Ohtsuka, Satoshi;Goettgens, Berthold;Niwa, Hitoshi;Smith, Austin
通讯作者：
Smith, Austin
影响因子：
64.8
作者：
Brons, I. Gabrielle M.;Smithers, Lucy E.;Vallier, Ludovic
通讯作者：
Vallier, Ludovic
影响因子：
21.3
作者：
Feng, Bo;Jiang, Jianming;Ng, Huck-Hui
通讯作者：
Ng, Huck-Hui