Oral Presentation ESA-SRB-NZSE-CaSR 2026 in conjunction with ENSA

EED is a novel epigenetic regulator of Leydig cell development and Sertoli cell function in the testis (143820)

Dylan Sloothaak 1 2 , Ellen Jarred 1 , Bianka Su 1 2 3 4 , Penny Whiley 1 , Natarsha Luu 1 2 , Reena Desai 5 , Mark Hedger 1 , David Handelsman 5 , Kate Loveland 1 2 , Robin Hobbs 3 4 , Patrick Western 1 2
  1. Centre for Endocrinology and Reproductive Health, Hudson Institute , Clayton, VIC, Australia
  2. Molecular and Translational Science, Monash University, Clayton, VIC, Australia
  3. School of Pharmacy and Biomedical Science, Adelaide University, Adelaide, South Australia, Australia
  4. Robinson Research Institute, Adelaide, South Australia, Australia
  5. ANZAC Research Institute , Concord, New South Wales, Australia

Background: Dynamic changes in epigenetic modifications are essential for regulating the expression of genes required for cell differentiation and function. Epigenetic mechanisms are often dysregulated in disease and have thus become a target for treatment. While various epigenetic modifiers are known to coordinate sex determination, little is known of the epigenetic mechanisms required to enable testicular cell differentiation. Polycomb Repressive Complex 2 (PRC2) catalyses the trimethylation of lysine 27 within histone 3 to supress developmental genes in a range of tissues, but its role in the testis is poorly understood. Therefore, we assessed the importance of PRC2 in testis development and function.

 

Methods: The essential PRC2 subunit, Eed, was conditionally deleted in testicular somatic cells in mice. Testicular phenotype was analysed using immunofluorescence and histological staining coupled with quantitative machine learning assisted approaches (n=3-6/genotype).

 

Results: Eed deletion significantly reduced testis weight by postnatal day 7 which persisted to adulthood, suggesting a role of PRC2 in regulating Sertoli cell proliferation and survival during postnatal development. Furthermore, microtubule structure and focal adhesion expression were altered in Sertoli cells, leading to disrupted germ cell transport throughout the epithelium. As a result, spermatogenesis was disrupted and immature germ cells detached from the epithelium, leading to an absence of mature sperm in the epididymis. In addition, Leydig and peritubular myoid cells displayed aberrant expression of steroidogenic and morphological markers, indicating that PRC2 may coordinate differentiation of Leydig and myoid cells from progenitor cells.

 

Conclusion: These findings demonstrate a crucial role of PRC2 in regulating the development and function of several testicular somatic cell types to support spermatogenesis. Our work provides insights into the epigenetic mechanisms that coordinate testis development, male fertility, and reproductive health. Furthermore, these findings indicate that EED inhibiting drugs or other environmental factors that disrupt PRC2 could detrimentally affect testicular function.