Defining the role of H4ac in mammalian embryogenesis and maternal aging

About This Grant

SUMMARY Gametes are terminally differentiated cells that carry the information required to establish a totipotent embryo. Epigenetic modifications are integral to maintaining this developmental plasticity, and drastic epigenetic reprogramming occurs soon after fertilization, enabling major transitions in potency. Furthermore, epigenetic dysregulation is a hallmark of aging; accumulation of faulty epigenetic marks contributes to lower oocyte quality and lower numbers of blastocysts formed from aged oocytes. However, the mechanisms by which epigenetic modifications guide reprogramming at fertilization and key transitions in early embryogenesis, and how these mechanisms decay with age, remain poorly understood, in part because of the difficulty in obtaining experimental material at these early stages. Using an ultra-low-scale CUT&Tag method that I developed, my preliminary studies showed that a specific acetylation state of histone H4, H4K12ac, is specifically recruited to SINE-containing active regulatory elements during ZGA and that loss of H4K12ac leads to embryonic arrest and failure to form blastocysts. Notably, H4K12ac is commonly overexpressed in aged oocytes. Activation- associated histone modifications, including several acetylation states of histone H4 (H4ac), are abundant in the zygote, where they are thought to be critical for decondensation of sperm DNA and zygotic genome activation (ZGA). Age-dependent changes in these epigenetic marks are linked to reduced fertility, and global levels of H4ac change with age. However, how H4ac directs distinct cellular transitions during embryogenesis and how defective H4ac regulation in aging could reduce gamete and embryo competence is not fully understood. I hypothesize that H4K12ac-mediated activation of SINEs is important for mammalian embryogenesis and dysregulation of H4K12ac contributes to reduced fertility with maternal aging. The goal of my project is to dissect the mechanism by which H4K12ac and other H4ac states direct embryogenesis and to understand how age-associated defects contribute to reduction of fertility. This investigation will provide crucial insights into early development and ways to extend the female fertility span.