Propagation of cellular memory through dormancy

Decades of work established the importance of dormant cells in reproduction and regeneration, however, a central unsolved question is how the cell propagates transcriptional memory and cellular identity through dormancy. Current approaches tend to characterize dormancy as a binary on-off switch. In contrast, a highly coordinated and precisely timed set of events are needed to successfully transition cells into dormancy, to maintain dormancy, and to exit it. In DOR-CODE, I will leverage the latest gene editing and genome profiling tools on an inducible and reversible embryonic dormancy model that I spearheaded (Bulut-Karslioglu et al, 2016, van der Weijden et al, 2022) to discover the genomic basis of dormancy. My mission is to reveal the temporal regulatory code of dormancy - ‘DOR-CODE’ - without which cellular identity cannot be propagated through time.Recent work by us and others has started to reveal the epigenomic landscape of dormancy: a highly repressed state with elevated DNA and histone methylation and decreased transcriptional output. Cellular strategies to counteract this overall repressive state at regulatory sites at the correct times are key for the retention of developmental potential. Here, I will identify DNA and histone demethylation strategies to propagate transcriptional memory at key regulatory elements (Objectives 1&2) and connect locus-specific regulation (Objectives 1&2) to genome macro-organization (Objective 3). By building direct links between anabolic growth and genome regulation, I will demonstrate how timely gene reactivation is ensured to enable exit from dormancy. The conceptual leap and mechanistic insights resulting from DOR-CODE will (1) enhance our knowledge of embryonic dormancy and lay the foundation for better in vitro embryo preservation, (2) bring a fresh perspective to related systems such as regeneration, longevity, and cancer dormancy, and (3) fuel the research in my lab for decades to come.