EpiHTStem · Understanding the Maintenance and Heritability of Hematopoietic Stem Cell Memories: High-Throughput Drug Screening Meets Single-Cell Barcoding

During the development of multicellular organisms, cells from the same niche can be stochastically exposed to different signals and stimuli, and this variability has the potential to create epigenetic heterogeneity across cell populations. Importantly, this heterogeneity can confer individual cells different functional properties or different capacities to respond to the same stimuli. During the last decade, multiple laboratories have reported the existence of hematopoietic stem cell (HSC) clones with different functional behaviors that are transmitted to daughter cells. Very interestingly, these behaviors are transmitted to their progeny even after transplantation, suggesting that heritable epigenetic components are required to establish and maintain them. In this regard, some questions arise: Which epigenetic regulators are involved in the maintenance of these memories? Which regions associate with specific HSC fate memories? And, how heritable are different chromatin states in dividing HSCs? Until recently, we were very limited by the current technologies to answer these questions. Now, recent advances in single-cell lineage tracing, single-cell multiomics and ex-vivo HSC expansion cultures can be leveraged to provide a robust mechanistic understanding of clonal heritability of HSC fates and states. Consequently, this proposal aims to combine new lineage tracing techniques, multimodal single-cell sequencing and functional assays to: (1) create an atlas of clonally-heritable epigenetic states associated to specific functional HSC behaviors and (2) to identify epigenetic regulators that are required to maintain and transmit HSC memories associated with specific HSC fates.