The transcriptional activator Klf5 recruits p300-mediated H3K27ac for maintaining trophoblast stem cell pluripotency.

IF 5.3 2区 生物学 Q2 CELL BIOLOGY Journal of Molecular Cell Biology Pub Date : 2024-01-05 DOI:10.1093/jmcb/mjad045
Chengli Dou, Linhui Wu, Jingjing Zhang, Hainan He, Tian Xu, Zhisheng Yu, Peng Su, Xia Zhang, Junling Wang, Yi-Liang Miao, Jilong Zhou
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Abstract

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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转录激活因子 Klf5 可通过 p300 介导的 H3K27ac 来维持滋养层干细胞的全能性。
滋养层干细胞(TSCs)的有效增殖和分化对胎盘的发育不可或缺,而胎盘是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(ESC)中多能基因表达的激活有关,但其在TSCs中的功能却鲜为人知。在这里,我们发现Klf5敲除会导致TSC特异性核心基因下调,从而导致TSCs快速分化。同样,去除了Klf5的胚胎失去了在体外建立TSCs的能力。在分子水平上,Klf5优先占据近端启动子区域,并维持关键TSC特异基因的开放染色质结构。剥夺Klf5会影响p300(H3赖氨酸27乙酰化(H3K27ac)的主要组蛋白乙酰转移酶)的富集,并进一步降低H3K27ac在启动子区域的占据率,从而导致TSC多能基因的转录活性降低。因此,我们的研究结果凸显了Klf5调控TSC自我更新和分化的新机制,为了解胎盘发育和提高妊娠率提供了参考。
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来源期刊
CiteScore
9.60
自引率
1.80%
发文量
1383
期刊介绍: The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome. JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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