胆固醇侧链裂解酶
DNMT1型
DNA甲基化
发起人
甲基化
生物
CpG站点
滋养层
转录因子
内科学
基因表达
胎盘
信使核糖核酸
基因
遗传学
医学
怀孕
胎儿
作者
Yanan Zhu,Fan Pan,Xiao-Wen Gan,Yun Liu,Wangsheng Wang,Kang Sun
标识
DOI:10.1210/endocr/bqad195
摘要
Progesterone synthesized in the placenta is essential for pregnancy maintenance. CYP11A1 is a key enzyme in progesterone synthesis, and its expression increases greatly during trophoblast syncytialization. However, the underlying mechanism remains elusive. Here, we demonstrated that passive demethylation of CYP11A1 promoter accounted for the upregulation of CYP11A1 expression during syncytialization with the participation of the transcription factor C/EBPα. We found that the methylation rate of a CpG locus in CYP11A1 promoter was significantly reduced along with decreased DNA methyltransferase 1 (DNMT1) expression and its enrichment at CYP11A1 promoter during syncytialization. DNMT1 overexpression not only increased the methylation of this CpG locus in CYP11A1 promoter, but also decreased CYP11A1 expression and progesterone production. In silico analysis disclosed multiple C/EBPα binding sites in both CYP11A1 and DNMT1 promoters. C/EBPα expression and its enrichments at both DNMT1 and CYP11A1 promoters were significantly increased during syncytialization. Knocking-down C/EBPα expression increased DNMT1 while decreased CYP11A1 expression during syncytialization. Conclusively, C/EBPα plays a dual role in the regulation of CYP11A1 during syncytialization. C/EBPα not only drives CYP11A1 expression directly, but also indirectly through down-regulation of DNMT1, which leads to decreased methylation in the CpG locus of CYP11A1 promoter, resulting in increased progesterone production during syncytialization.
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