PARP1 regulates establishment of the ovarian reserve and age at natural menopause

Menopause not only signifies the end of a woman’s reproductive life, but also brings about significant changes in both mental and physical health due to hormonal changes. Age of natural menopause (ANM) and reproductive lifespan is determined by the formation and subsequent depletion of follicles in females. In this study, we identified a robust association between a common functional missense variant in PARP1 and age at menopause in a sample of 201,323 women. Using an in vitro model to generate primordial germ cells - the precursors of sperm and oocytes- we report that Parp1 affects PGCs in two different ways. Our identified missense variant (V762A) significantly reduces the germ cell population by enhanced DNA binding resulting in increased apoptosis. Conversely, deletion of Parp1 results in an increased population of PGCs and proteomic analysis revealed that transcription factors that drive PGC formation show increased expression in precursor cells. This is caused by increased transcription of Rhox genes ( Rhox2A , Rhox6 and Rhox9 ), implicating Parp1 in downregulation of genes that determine PGC fate. We propose that Parp1 regulates PGC fate and that its increased chromatin association (‘trapping’) causes a decreased population of PGCs, thereby providing a molecular cause of the earlier onset menopause on female carriers of the variant.