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Theranostics 2024; 14(4):1371-1389. doi:10.7150/thno.89878 This issue Cite

Research Paper

Polycomb repressive complex 1 modulates granulosa cell proliferation in early folliculogenesis to support female reproduction

Meng Gao^1,*, Tuo Zhang^2,*, Tengxiang Chen², Ziqi Chen¹, Zijian Zhu¹, Yang Wen³, Shaogang Qin¹, Yibing Bao¹, Ting Zhao¹, Hengxing Li¹, Longping Liu⁴, Ming Hao⁴, Jianbin Wang⁴, Fengchao Wang⁵, Haibin Wang⁶, Bo Zhou¹, Hua Zhang¹, Guoliang Xia^1,7,✉, Chao Wang^1,✉

1. State Key Laboratory of Farm Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
2. Guizhou Provincial Key Laboratory of Pathogenesis & Drug Research on Common Chronic Diseases, Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou Province, 550025, China.
3. State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China.
4. School of Life Sciences, Tsinghua University, Beijing, 100084, China.
5. Transgenic Animal Center, National Institute of Biological Sciences, Beijing, 102206, China.
6. Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, 361005, China.
7. Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, College of Life Science, Ningxia University, Yinchuan, 750021, China.
^* These authors contributed equally.

✉ Corresponding authors: wangcamcom (W.C.); glxiachinacom (X.G.L.).

Abstract

Rationale: Premature ovarian insufficiency (POI) is an accelerated reduction in ovarian function inducing infertility. Folliculogenesis defects have been reported to trigger POI as a consequence of ovulation failure. However, the underlying mechanisms remain unclear due to the genetic complexity and heterogeneity of POI.

Methods: We used whole genome sequencing (WGS), conditional knockout mouse models combined with laser capture microdissection (LCM), and RNA/ChIP sequencing to analyze the crucial roles of polycomb repressive complex 1 (PRC1) in clinical POI and mammalian folliculogenesis.

Results: A deletion mutation of MEL18, the key component of PRC1, was identified in a 17-year-old patient. However, deleting Mel18 in granulosa cells (GCs) did not induce infertility until its homolog, Bmi1, was deleted simultaneously. Double deficiency of BMI1/MEL18 eliminated PRC1 catalytic activity, upregulating cyclin-dependent kinase inhibitors (CDKIs) and thus blocking GC proliferation during primary-to-secondary follicle transition. This defect led to damaged intercellular crosstalk, eventually resulting in gonadotropin response failure and infertility.

Conclusions: Our findings highlighted the pivotal role of PRC1 as an epigenetic regulator of gene transcription networks in GC proliferation during early folliculogenesis. In the future, a better understanding of molecular details of PRC1 structural and functional abnormalities may contribute to POI diagnosis and therapeutic options.

Keywords: Folliculogenesis, PRC1, CDKI, granulosa cell proliferation, infertility, POI

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