Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan 430070, China.
J Mol Cell Biol. 2024 Jan 5;15(7). doi: 10.1093/jmcb/mjad045.
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.
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，而胎盘的正常发育是维持妊娠期间胎儿正常生长的关键。Krüppel 样因子 5（Klf5）参与胚胎干细胞（ESCs）中多能性基因表达的激活，但它在 TSCs 中的功能知之甚少。在这里，我们发现 Klf5 敲低导致核心 TSC 特异性基因下调，从而导致 TSCs 的快速分化。一致地，Klf5 耗尽的胚胎失去了在体外建立 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染色质结构。Klf5 的缺失损害了主要组蛋白乙酰转移酶 H3 赖氨酸 27 乙酰化（H3K27ac）的 p300 的富集，进一步降低了启动子区域的 H3K27ac 占有率，导致 TSC 多能性基因的转录活性降低。因此，我们的发现强调了 Klf5 在调节 TSCs 的自我更新和分化中的新机制，并为理解胎盘发育和提高妊娠率提供了参考。
