The role of ZCWPW1 in meiosis

Abstract: While generation of sperm and eggs through meiosis is exquisitely coordinated and tightly regulated, chromosome segregation is remarkably error prone. In humans it is estimated that ~5% of sperm and ~30% of oocytes have the wrong chromosome complement - known as aneuploidy. As such, errors in meiotic chromosome segregation are a leading cause of mental disability, miscarriage, and infertility. In mammals, critical steps that ensure faithful chromosome segregation include generation of programmed DNA double- stranded breaks (DSBs) at PRDM9 hotspots that are enriched for dual Histone H3 lysine 4 and lysine 36 trimethylation (K4/H3K36me3), the pairing of parental chromosomes (homologs), the co-alignment of homologs lengthwise, and the tethering of homologs by crossing over – the exchange of chromosome arms between homologs. Despite this wealth in knowledge, a key gap in knowledge in this process is how PRDM9-dependent dual H3K4/H3K36me3 modifications influence homolog pairing and recombination. We and others have shown that ZCWPW1, a dual histone methylation reader, is enriched at PRDM9 target sites, has no effect on the number or location of DSBs, but may be important for DSB repair. More specifically, our preliminary data suggest that ZCWPW1 may be required for efficient homolog pairing which when compromised culminates in chromosome entanglements, DSB repair defects, and ultimately chromosome mis-segregation and infertility. Therefore, we propose a comprehensive and integrative analysis using genetic, genomic, molecular, and biochemical approaches to dissect the role of ZCWPW1 in homolog pairing and recombination. Overall, these studies will provide fundamental knowledge about meiotic chromosome dynamics and a mechanistic understanding of the role of ZCWPW1 in mammalian meiosis.