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BRG1通过增强糖酵解代谢提高重编程效率。

BRG1 improves reprogramming efficiency by enhancing glycolytic metabolism.

作者信息

Ren Xuan, Huang Shihai, Xu Jianchun, Xue Qingsong, Xu Tairan, Shi Deshun, Ma Shinan, Li Xiangping

机构信息

Guangxi Key Laboratory of Animal Breeding and Disease Control, College of Animal Science and Technology, Guangxi University, Nanning, 530005, China.

College of Life Science and Technology, Guangxi University, Nanning, 530005, China.

出版信息

Cell Mol Life Sci. 2024 Dec 6;81(1):482. doi: 10.1007/s00018-024-05527-2.

DOI:10.1007/s00018-024-05527-2
PMID:39643758
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11624181/
Abstract

BRG1 has been found to promote the generation of induced pluripotent stem cells (iPSCs) by regulating epigenetic modifications or binding to transcription factors, however, the role of BRG1 on the cellular metabolism during reprogramming has not been reported. In this study, we found that BRG1 improved the efficiency of porcine iPSC generation, and upregulated the expression of pluripotency-related factors. Further analysis revealed that BRG1 promoted cellular glycolysis, and increased levels of glycolysis-related metabolites. It enhanced the transcriptional activity of glycolysis-related gene HK2, PKM2, and PFK-1 promoters, and decreased the enrichment of H3K9me3 in glycolysis- and pluripotency-related gene promoters. BRG1 also increased the phosphorylation level at the Ser473 site of AKT protein. The specific PI3K/AKT signaling pathway inhibitor, LY294002, impaired the generation of porcine iPSCs, downregulated the expression of pluripotency-related factors, and inhibited cellular glycolysis, overexpressing BRG1 rescued those changes caused by LY294002 treatment. In addition, the glycolysis inhibitor 2-DG and BRG1 inhibitor PFI-3 had similar effects to LY294002. The above results suggest that overexpression of BRG1 promotes the generation of porcine iPSCs by facilitating glycolytic reprogramming through the PI3K/AKT signaling pathway.

摘要

研究发现，BRG1可通过调节表观遗传修饰或与转录因子结合来促进诱导多能干细胞（iPSC）的产生，然而，BRG1在重编程过程中对细胞代谢的作用尚未见报道。在本研究中，我们发现BRG1提高了猪iPSC的产生效率，并上调了多能性相关因子的表达。进一步分析表明，BRG1促进细胞糖酵解，并增加糖酵解相关代谢物的水平。它增强了糖酵解相关基因HK2、PKM2和PFK-1启动子的转录活性，并降低了糖酵解和多能性相关基因启动子中H3K9me3的富集。BRG1还增加了AKT蛋白Ser473位点的磷酸化水平。特异性PI3K/AKT信号通路抑制剂LY294002损害了猪iPSC的产生，下调了多能性相关因子的表达，并抑制了细胞糖酵解，过表达BRG1可挽救LY294002处理引起的这些变化。此外，糖酵解抑制剂2-DG和BRG1抑制剂PFI-3具有与LY294002相似的作用。上述结果表明，BRG1的过表达通过PI3K/AKT信号通路促进糖酵解重编程，从而促进猪iPSC的产生。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/6ed10a385568/18_2024_5527_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/592db2d8eea6/18_2024_5527_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/98060ed001d8/18_2024_5527_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/fffb2dc0bc87/18_2024_5527_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/2c434d7ac020/18_2024_5527_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/f1e56cd08cc6/18_2024_5527_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/ff11cfe31967/18_2024_5527_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/1054ec095325/18_2024_5527_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/6ed10a385568/18_2024_5527_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/592db2d8eea6/18_2024_5527_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/98060ed001d8/18_2024_5527_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/fffb2dc0bc87/18_2024_5527_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/2c434d7ac020/18_2024_5527_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/f1e56cd08cc6/18_2024_5527_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/ff11cfe31967/18_2024_5527_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/1054ec095325/18_2024_5527_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f52d/11624181/6ed10a385568/18_2024_5527_Fig8_HTML.jpg

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本文引用的文献

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Overexpression of BRG1 improves early development of porcine somatic cell nuclear transfer embryos.BRG1 的过表达可提高猪体细胞核移植胚胎的早期发育。
Theriogenology. 2024 Mar 15;217:51-63. doi: 10.1016/j.theriogenology.2024.01.003. Epub 2024 Jan 9.
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