Intrauterine hyperglycemia impairs mouse primordial germ cell development and fertility by sex-specific epigenetic reprogramming interference.

IF 12.5 1区 生物学 Q1 CELL BIOLOGY
Jiangshan Cong, Qing Li, Yangyang Li, Minghao Li, Yan Shi, Peiran Hu, Xidi Yin, Qianyun Zhang, Jianzhong Sheng, Jinsong Li, Guolian Ding, Yu Zhang, Hefeng Huang
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引用次数: 0

Abstract

Adverse intrauterine environments, such as hyperglycemia, impair sexual reproduction and species continuity, yet the underlying mechanisms remain poorly understood. In this study, we demonstrated that intrauterine hyperglycemia significantly disrupted primordial germ cell (PGC) development, especially in female offspring, thus reducing fertility. Using Oct4-EGFP transgenic mice with intrauterine hyperglycemia exposure, we revealed that hyperglycemia compromised sexually specific chromatin accessibility and DNA methylation reprogramming during PGC development. Particularly, in female PGCs, hyperglycemia leads to the aberrant retention of chromatin accessibility at pluripotency gene promoters such as Nanog and Tfap2c, inhibiting proper gene silencing and blocking the initiation of meiosis, which ultimately hinders oocyte maturation. Conversely, male PGCs exhibit less severe changes in chromatin accessibility and gene transcription. Intriguingly, the global DNA methylation reconstruction is impaired in male PGCs, particularly in key imprinted gene regions, suggesting potential developmental ramifications for later stages and even subsequent generations. Particularly, our findings indicate that intrauterine hyperglycemia adversely affects sex differentiation in PGCs by disrupting the expression of critical sex-determining transcription factors. Collectively, these findings highlight how intrauterine hyperglycemia interferes with sex-specific epigenetic reprogramming during PGC development, leading to abnormal germ cell development, reduced fertility, and adverse intergenerational effects.

宫内高血糖通过性别特异性表观遗传重编程干扰损害小鼠原始生殖细胞发育和生育能力。
不良的宫内环境,如高血糖,会损害有性生殖和物种的连续性,但其潜在的机制仍然知之甚少。在这项研究中,我们证明了宫内高血糖显著破坏了原始生殖细胞(PGC)的发育,特别是在雌性后代中,从而降低了生育能力。通过使用宫内高血糖暴露的Oct4-EGFP转基因小鼠,我们发现高血糖在PGC发育过程中损害了性特异性染色质可及性和DNA甲基化重编程。特别是,在女性PGCs中,高血糖导致多能基因启动子(如Nanog和Tfap2c)染色质可及性的异常保留,抑制了适当的基因沉默,阻断了减数分裂的开始,最终阻碍了卵母细胞成熟。相反,男性PGCs在染色质可及性和基因转录方面表现出不太严重的变化。有趣的是,男性PGCs的整体DNA甲基化重建受损,特别是在关键的印迹基因区域,这表明对后期甚至后代的潜在发育影响。特别是,我们的研究结果表明,宫内高血糖通过破坏关键的性别决定转录因子的表达,对PGCs的性别分化产生不利影响。总之,这些发现强调了宫内高血糖如何干扰PGC发育过程中性别特异性的表观遗传重编程,导致生殖细胞发育异常、生育能力降低和不良的代际影响。
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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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