3011 – EPIGENETIC PROGRAMMING PREDICTS HEMATOPOIETIC STEM CELL FATE RESTRICTION AND PLATELET DIFFERENTIATION KINETICS

Hematopoietic stem cells (HSCs) are a self-renewing primitive cell type that generates definitive blood cells throughout the mammalian lifespan. While HSC has been viewed as a multipotent population, clonal analysis using either barcode-based lineage tracing or single cell repopulating assays has identified distinct HSC subsets with biased lineage output. However, how HSC fate-restriction is molecularly programmed and what role do different HSC subsets play in physiological and pathological conditions, remains an open question. Here we report the molecular profiles of HSC subtypes with defined lineage restriction at both transcription and epigenetic levels, and show that platelet-restricted HSCs have distinct molecular lineage priming state from multilineage HSCs. The lymphoid fate of multilineage HSCs is not transcriptionally programmed, but determined by increased accessibility of selective lymphoid-associated enhancers that regulate genes activated immediately downstream of the HSC compartment. In contrast, platelet-restricted HSCs show upregulated platelet-specific gene expression and chromatin accessibility. This enhanced platelet-lineage priming is inherited by the distinct platelet-producing progenitors selectively generated by HSC subtypes, leading to faster formation, but lower output of platelets from platelet-restricted HSCs compared to multilineage HSCs. Overall, our data suggest that epigenetic priming can accurately predict HSC fate restriction and the trade-off between speed and quantity during platelet differentiation from HSCs. These findings highlight the importance of the epigenome in cellular fate decisions, and provide a paradigm for the study of multipotent stem cells of other tissues in general.