18 March 2022
Bluma Lesch
School of Medicine
Yale University
The germ line offers a unique opportunity to discover mechanisms that control long-term epigenetic memory. Not only do germ cells harbor the physical material that is transmitted across generations, but they also subject their chromosomes to unusually drastic physical changes, including homolog pairing and sperm head compaction. Together, these features of the germ line demand specialized mechanisms that either safeguard stability of epigenetic information or ensure its removal and reprogramming. I will discuss features of epigenetic memory in the germ line at two time scales: the organismal time scale, where regulatory states are retained or reset across single fertilization events, and the evolutionary time scale, where regulatory states are retained or modified across millions of individuals’ life cycles. In the first case, I will discuss a mouse model where paternal germline loss of an epigenetic regulator results in elevated tumor frequency in offspring, and describe our efforts to understand how altered epigenetic regulation in the mutant germline disrupts the transcriptional networks that contribute to tumorigenesis. In the second, I will discuss the question of how new epigenetic states emerge during evolution. Biochemically, establishing an epigenetic environment requires complex, multifactorial interactions among proteins and DNA sequences, but most evolutionary change occurs slowly and in a stepwise manner. We are attempting to computationally and experimentally reconstruct emergence of bivalency, a biochemically complex and developmentally important epigenetic state.