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

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.

P62 promotes FSH-induced antral follicle formation by directing degradation of ubiquitinated WT1

“…Oocytes are generally separated by the mouth-controlled glass pipette, and the remaining liquid was centrifuged to obtain GCs. The process of Ovary isolation and GCs collection was described in our previous study [ 68 ].…”

“…The process of immunofluorescence and immunohistochemistry was described in our previous study [ 68 ]. The ovaries were fixed in 4% paraformaldehyde (PFA) overnight, embedded in paraffin wax and continuously sliced at seven microns.…”

“…Apoptotic cells were detected using the TUNEL BrightGreen Apoptosis Detection kit (Vazyme Biotech Co., Ltd, A112). The process of BrdU and TUNEL assays were described in our previous study [ 68 , 74 ].…”

HTR1B regulates mitochondrial homeostasis and mitophagy by activating the ERK/ MAPK signalling pathway during human embryonic arrest

“…For each sample, 3–5 random 20 × fields of view were scored. Digital images were inputted into Image J software for quantitative image analysis [ 20 ].…”