Metformin promotes female germline stem cell proliferation by upregulating Gata-binding protein 2 with histone β-hydroxybutyrylation.
Metformin promotes female germline stem cell proliferation by upregulating Gata-binding protein 2 with histone β-hydroxybutyrylation.
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DOI：
10.1186/s13287-023-03360-1
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发表时间：
2023-05-26
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
--
作者：
二甲双胍作为临床一线抗糖尿病药物，可延长模型动物寿命，促进细胞增殖。然而，增殖表型的分子机制，特别是在表观遗传学方面，很少有报道。本研究旨在研究二甲双胍对女性生殖系干细胞（FGSCs）体内外的生理作用，揭示二甲双胍β-羟基丁基化的表观遗传修饰作用，并确定组蛋白H2B Lys5 β-羟基丁基化（H2BK5bhb）在gta结合蛋白2 （Gata2）介导的FGSCs增殖促进中的机制。通过腹腔注射和组织形态学观察二甲双胍的生理作用。通过细胞计数、细胞活力、细胞增殖试验、蛋白修饰组学、转录组学、染色质免疫沉淀测序等方法对体外FGSCs进行表型和机制研究。我们发现二甲双胍治疗增加了FGSCs的数量，促进了小鼠卵巢的卵泡发育，并增强了FGSCs的体外增殖活性。蛋白质修饰的定量组学分析显示，二甲双胍处理FGSCs后，H2BK5bhb增加。结合H2BK5bhb染色质免疫沉淀和转录组测序，我们发现Gata2可能是二甲双胍调节FGSC发育的靶基因。随后的实验表明，Gata2促进了FGSC的增殖。我们的研究结果通过结合组蛋白表观遗传学和表型分析，为二甲双胍在FGSCs中的作用提供了新的机制理解，强调了二甲双胍- h2bk5bhb - gata2通路在细胞命运决定和调控中的作用。在线版本包含补充材料，下载地址：10.1186/s13287-023-03360-1。
Metformin as a first-line clinical anti-diabetic agent prolongs the lifespan of model animals and promotes cell proliferation. However, the molecular mechanisms underlying the proliferative phenotype, especially in epigenetics, have rarely been reported. The aim of this study was to investigate the physiological effects of metformin on female germline stem cells (FGSCs) in vivo and in vitro, uncover β-hydroxybutyrylation epigenetic modification roles of metformin and identify the mechanism of histone H2B Lys5 β-hydroxybutyrylation (H2BK5bhb) in Gata-binding protein 2 (Gata2)-mediated proliferation promotion of FGSCs. The physiological effects of metformin were evaluated by intraperitoneal injection and histomorphology. The phenotype and mechanism studies were explored by cell counting, cell viability, cell proliferation assay and protein modification omics, transcriptomics, chromatin immunoprecipitation sequencing in FGSCs in vitro. We found that metformin treatment increased the number of FGSCs, promoted follicular development in mouse ovaries and enhanced the proliferative activity of FGSCs in vitro. Quantitative omics analysis of protein modifications revealed that H2BK5bhb was increased after metformin treatment of FGSCs. In combination with H2BK5bhb chromatin immunoprecipitation and transcriptome sequencing, we found that Gata2 might be a target gene for metformin to regulate FGSC development. Subsequent experiments showed that Gata2 promoted FGSC proliferation. Our results provide novel mechanistic understanding of metformin in FGSCs by combining histone epigenetics and phenotypic analyses, which highlight the role of the metformin-H2BK5bhb-Gata2 pathway in cell fate determination and regulation. The online version contains supplementary material available at 10.1186/s13287-023-03360-1.
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影响因子：
5.9
作者：
Fatt M;Hsu K;He L;Wondisford F;Miller FD;Kaplan DR;Wang J
通讯作者：
Wang J
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影响因子：
4.6
作者：
Ding X;Liu G;Xu B;Wu C;Hui N;Ni X;Wang J;Du M;Teng X;Wu J
通讯作者：
Wu J
影响因子：
6.1
作者：
Fauser, BCJM;Chang, J;Lobo, R
通讯作者：
Lobo, R
影响因子：
8.5
作者：
Bai, Y.;Yu, M.;Hua, J.
通讯作者：
Hua, J.
DOI：
10.1016/j.bbrc.2018.02.191
发表时间：
2018-03-25
影响因子：
3.1
作者：
Na, Hyun-Jin;Pyo, Jung-Hoon;Yoo, Mi-Ae
通讯作者：
Yoo, Mi-Ae