Dissecting the role of ZCWPW1 in oocyte quality, fertility and ovarian physiology.

PROJECT SUMMARY: Gametogenesis relies on a specialized cell division called meiosis, where homologous chromosomes pair together, exchange genetic information through induced DNA double-strand breaks (DSBs) and separate into haploid daughter cells. The sites of homologous recombination (HR) events in mammals, called crossovers (COs), are determined by PRDM9, an H3K4/K36 methyltransferase. Recent evidence highlights the significance of symmetric PRDM9-dependent modifications—chromatin modifications on both homologs at the same genomic loci—for early inter-chromosomal pairing events and subsequent CO formation. However, it remains unknown how the symmetric PRDM9-dependent modifications directly influence meiotic homolog associations and downstream DSB repair. Our team and others have identified a dual H3K4/K36me3 reader, ZCWPW1, that may coordinate PRDM9-dependent modifications and downstream recombination. Consistent with this model, Zcwpw1-/- males are sterile, with their spermatocytes displaying a failure to repair DSBs and display chromosomal aberrations, including elevated rates of heterologous association. In contrast, Zcwpw1-/- females, while initially fertile, become sterile at 6-8 months due to premature ovarian failure. Here we will examine the role of ZCWPW1 in female meiosis. This milder phenotype in females allows us to define ZCWPW1's role in homolog pairing and recombination and its contribution to meiotic prophase progression and oocyte elimination or survival. To dissect the role of ZCWPW1 in homolog pairing and DSB repair, we propose a comprehensive and integrative analysis of ZCWPW1 function using a series of genetic models and molecular techniques. Overall, these studies will provide fundamental insights into female meiotic chromosome dynamics and a mechanistic understanding of the role of ZCWPW1 in oocyte quality control and ovarian reserve establishment and maintenance.