The transcriptional activator Klf5 recruits p300-mediated H3K27ac for maintaining trophoblast stem cell pluripotency.
The transcriptional activator Klf5 recruits p300-mediated H3K27ac for maintaining trophoblast stem cell pluripotency.
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转录激活因子Klf5募集p300介导的H3K27ac以维持滋养层干细胞的多能性。
DOI：
10.1093/jmcb/mjad045
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发表时间：
2024-01-05
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
滋养层干细胞（TSCs）的有效增殖和分化对于胎盘的发育是必不可少的，这是在孕期维持胎儿正常生长的关键。Kruppel样因子5（Klf5）与胚胎干细胞（ESCs）中多能性基因表达的激活有关，然而其在TSCs中的功能却鲜为人知。在此，我们发现Klf5的敲低导致核心TSC特异性基因的下调，从而引起TSCs的快速分化。一致地，Klf5缺失的胚胎丧失了在体外建立TSCs的能力。在分子水平上，Klf5优先占据关键TSC特异性基因的近端启动子区域并维持开放的染色质结构。Klf5的缺失损害了p300（一种主要的组蛋白H3赖氨酸27乙酰化（H3K27ac）的乙酰转移酶）的富集，并进一步降低了H3K27ac在启动子区域的占据，导致TSC多能性基因的转录活性降低。因此，我们的研究结果强调了Klf5在调节TSCs自我更新和分化中的一种新机制，并为理解胎盘发育和提高受孕率提供了参考。
The effective proliferation and differentiation of trophoblast stem cells (TSCs) is indispensable for the development of the placenta, which is the key to maintaining normal fetal growth during pregnancy. Kruppel-like factor 5 (Klf5) is implicated in the activation of pluripotency gene expression in embryonic stem cells (ESCs), yet its function in TSCs is poorly understood. Here, we showed that Klf5 knockdown resulted in the downregulation of core TSC-specific genes, consequently causing rapid differentiation of TSCs. Consistently, Klf5-depleted embryos lost the ability to establish TSCs in vitro. At the molecular level, Klf5 preferentially occupied the proximal promoter regions and maintained an open chromatin architecture of key TSC-specific genes. Deprivation of Klf5 impaired the enrichment of p300, a major histone acetyl transferase of H3 lysine 27 acetylation (H3K27ac), and further reduced the occupancy of H3K27ac at promoter regions, leading to decreased transcriptional activity of TSC pluripotency genes. Thus, our findings highlight a novel mechanism of Klf5 in regulating the self-renewal and differentiation of TSCs and provide a reference for understanding placental development and improving pregnancy rates.
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