UC Davis

Worldwide, over 15% of couples have difficulty conceiving a child. Long-term fertility in males is governed by spermatogenesis, the developmental program responsible for producing mature sperm. Sperm were once viewed primarily as carriers of paternal DNA, but they also carry epigenetic information that can influence fertilization and early embryonic development. This information is established through the remodeling of chromatin, the combination of DNA and associated proteins, as germ cells develop. However, why and how molecular regulators and environmental conditions shape the epigenome remains incompletely understood.To address this gap in knowledge, I investigated how intrinsic and environmental factors influence the epigenetic trajectory of the male germline. I approached this biological question using two complementary mouse models: genetic deletion of a chromatin regulator, ATF7IP2/MCAF2, and dietary folate deficiency. By independently assessing each model using a combination of imaging and genome-wide analysis of gene expression and chromatin, I found that disruption of either factor resulted in distinct, but converging cellular and epigenetic changes in spermatogenesis. Genetic deletion of ATF7IP2/MCAF2 revealed an unexpected role in gene regulation and epigenetic reprograming in male meiosis. These findings also refined our understanding of how meiotic checkpoints respond to disrupted chromatin regulation. In the second model, paternal folate deficiency altered germ cell development, meiotic gene expression and various chromatin features in meiosis. Together, these findings identify meiosis as a period of both epigenetic vulnerability and responsiveness. I propose that meiosis functions as a metabolic sensing window during which nutritional conditions can influence the chromatin landscape as it is being extensively reprogrammed. This conceptual framework helps explain how molecular regulation and environmental exposures interact to shape sperm development and potentially influence the information transmitted to the next generation.