DNA methylation mediated RSPO2 to promote follicular development in mammals.
DNA methylation mediated RSPO2 to promote follicular development in mammals.
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DNA甲基化介导的RSPO2促进哺乳动物卵泡发育
DOI：
10.1038/s41419-021-03941-z
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发表时间：
2021-06-26
影响因子：
9
通讯作者：
Yuan X
中科院分区：
文献类型：
--
作者：
Zhou X;He Y;Li N;Bai G;Pan X;Zhang Z;Zhang H;Li J;Yuan X
在雌性哺乳动物中，颗粒细胞 (GC) 的增殖、凋亡和雌二醇-17β (E2) 分泌已决定卵泡的命运。据报道，Wnt信号通路的DNA甲基化和RSPO2基因参与GC的存活和卵泡发育。然而，DNA甲基化如何调节RSPO2表达并参与卵泡发育的分子机制尚不清楚。本研究发现，在卵泡发育过程中，RSPO2的mRNA和蛋白水平显着升高，但RSPO2启动子的DNA甲基化水平逐渐下降。抑制DNA甲基化或敲低DNMT1可以降低RSPO2启动子中CpG岛(CGI)的甲基化水平，并上调猪GC中RSPO2的表达水平。 RSPO2启动子中-758/-749和-563/-553区域的低甲基化促进了转录因子E2F1的占据，并促进了RSPO2的转录活性。此外，RSPO2通过增加PCNA、CDK1和CCND1的表达水平促进GCs的增殖，通过增加CYP19A1和HSD17B1的表达水平促进GCs的E2分泌，通过降低Caspase3、cleaved Caspase3、cleaved Caspase8、cleaved Caspase9、cleaved PARP和BAX的表达水平抑制GCs凋亡。此外，RSPO2敲低可通过降低体内Wnt信号通路相关基因（LGR4和CTNNB1）的表达水平，促进GC细胞凋亡，阻碍卵泡发育，并延迟青春期的开始。综上所述，RSPO2启动子中-758/-749和-563/-553区域的低甲基化促进了E2F1的占据，增强了RSPO2的转录，进一步促进GC的增殖和E2的分泌，抑制GC的凋亡，最终通过Wnt信号通路改善卵泡的发育。本研究将为进一步探索卵泡发育过程中DNA甲基化介导的RSPO2通路提供有用的信息。
In female mammals, the proliferation, apoptosis, and estradiol-17β (E2) secretion of granulosa cells (GCs) have come to decide the fate of follicles. DNA methylation and RSPO2 gene of Wnt signaling pathway have been reported to involve in the survival of GCs and follicular development. However, the molecular mechanisms for how DNA methylation regulates the expression of RSPO2 and participates in the follicular development are not clear. In this study, we found that the mRNA and protein levels of RSPO2 significantly increased during follicular development, but the DNA methylation level of RSPO2 promoter decreased gradually. Inhibition of DNA methylation or DNMT1 knockdown could decrease the methylation level of CpG island (CGI) in RSPO2 promoter and upregulate the expression level of RSPO2 in porcine GCs. The hypomethylation of −758/−749 and −563/−553 regions in RSPO2 promoter facilitated the occupancy of transcription factor E2F1 and promoted the transcriptional activity of RSPO2. Moreover, RSPO2 promoted the proliferation of GCs with increasing the expression level of PCNA, CDK1, and CCND1 and promoted the E2 secretion of GCs with increasing the expression level of CYP19A1 and HSD17B1 and inhibited the apoptosis of GCs with decreasing the expression level of Caspase3, cleaved Caspase3, cleaved Caspase8, cleaved Caspase9, cleaved PARP, and BAX. In addition, RSPO2 knockdown promoted the apoptosis of GCs, blocked the development of follicles, and delayed the onset of puberty with decreasing the expression level of Wnt signaling pathway-related genes (LGR4 and CTNNB1) in vivo. Taken together, the hypomethylation of −758/−749 and −563/−553 regions in RSPO2 promoter facilitated the occupancy of E2F1 and enhanced the transcription of RSPO2, which further promoted the proliferation and E2 secretion of GCs, inhibited the apoptosis of GCs, and ultimately ameliorated the development of follicles through Wnt signaling pathway. This study will provide useful information for further exploration on DNA-methylation-mediated RSPO2 pathway during follicular development.
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