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PIAS4调节猪胚胎干细胞的多能性退出和细胞命运决定。

PIAS4 regulates pluripotency exit and cell fate commitment in porcine embryonic stem cells.

作者信息

Qin Wei, Wang Yu, Duan Hongfei, Li Qiao, Tao Dagang, Su Peng, Wu Linhui, Li Delong, Xu Tian, Xie Shengsong, Zhang Xia, Zhou Jilong, Miao Yi-Liang

机构信息

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.

出版信息

Fundam Res. 2024 Nov 12;5(4):1556-1569. doi: 10.1016/j.fmre.2024.10.016. eCollection 2025 Jul.

DOI:10.1016/j.fmre.2024.10.016
PMID:40777776
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12327875/
Abstract

Post-translational modifications (PTMs) are dynamic processes that regulate cell states by enhancing proteome diversity. However, the overall impact of PTMs on pluripotency exit in porcine embryonic stem cells (pESCs) remains largely unknown. Here, we present a systematic assay to identify E3 ubiquitin ligases for pluripotency exit by using CRISPR/Cas9 pooled screening and identified PIAS4 as a major regulator of pluripotency exit, as the cell differentiation was significantly impaired upon PIAS4 depletion in pESCs. PIAS4 shows a high degree of genomic occupation in promoter regions, particularly in key pluripotency maintenance genes. Moreover, we found that PIAS4 was recruited to the gene promoter marked by H3K4me3 and interacted with lysine demethylase KDM5B via SUMOylation, thereby affecting the stability of KDM5B and further facilitating the regulation of H3K4me3-mediated lineage-specific genes. Together, our findings reveal a regulatory mechanism by which PIAS4 modulates H3K4me3 modification on development-related genes, subsequently influencing pluripotency exit and cell fate commitment by interacting with KDM5B in pESCs.

摘要

翻译后修饰（PTMs）是通过增强蛋白质组多样性来调节细胞状态的动态过程。然而，PTMs对猪胚胎干细胞（pESCs）多能性退出的总体影响在很大程度上仍不清楚。在这里，我们提出了一种系统的检测方法，通过使用CRISPR/Cas9混合筛选来鉴定参与多能性退出的E3泛素连接酶，并确定PIAS4是多能性退出的主要调节因子，因为在pESCs中PIAS4缺失时细胞分化会显著受损。PIAS4在启动子区域表现出高度的基因组占据，特别是在关键的多能性维持基因中。此外，我们发现PIAS4被招募到以H3K4me3标记的基因启动子上，并通过SUMO化与赖氨酸去甲基化酶KDM5B相互作用，从而影响KDM5B的稳定性，并进一步促进对H3K4me3介导的谱系特异性基因的调控。总之，我们的研究结果揭示了一种调节机制，即PIAS4通过调节发育相关基因上的H3K4me3修饰，随后通过与pESCs中的KDM5B相互作用来影响多能性退出和细胞命运决定。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/c168c365b501/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/518b31d9ff71/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/a545a4b5144e/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/bf4100139e2b/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/0b49219daf51/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/c9acf78a293b/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/6e229173f0e5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/c168c365b501/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/518b31d9ff71/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/a545a4b5144e/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/bf4100139e2b/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/0b49219daf51/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/c9acf78a293b/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/6e229173f0e5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1cf1/12327875/c168c365b501/gr6.jpg

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本文引用的文献

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SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites.
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Nucleic Acids Res. 2021 Feb 26;49(4):1951-1971. doi: 10.1093/nar/gkab032.
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Evaluating totipotency using criteria of increasing stringency.用越来越严格的标准评估全能性。
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