The Epi-Dev project will investigate the epigenetic and transcriptional mechanisms underlying lymphoid lineage specification in mammals. Our consortium will use a comparative human/mouse experimental strategy combining functional analyses and high throughput transcriptomic and epigenomic studies. Human studies will aim to investigate the bases of lymphoid priming in multipotent progenitors and to characterize the signaling pathways and gene networks driving the differential emergence of IL7 receptor (CD127) positive or negative lymphoid progenitors. Mouse studies conducted in parallel will also aim to dissect lymphoid priming and subsequent lymphoid diversification in the fetal liver. Single-cell comparative transcriptomics will then be used to define the developmental trajectories of human and mouse lymphoid progenitors. Overall, the Epi-Dev project will provide a roadmap of the early steps of lymphoid differentiation and will distinguish species-specific regulatory mechanisms from those that have been conserved through evolution. Ultimately, this project will contribute to a better understanding of the developmental plasticity and functional properties of the cells from which hematological malignancies originate and help unravel the perturbations of lymphoid differentiation associated with pathologic conditions and aging.