Single-cell transcriptomic resolution of stem cells and their developmental trajectories in the hippocampus reveals epigenetic control of cell state perseverance

Abstract Despite conceptual research on hippocampus development and the application of single-cell-resolved technologies, the nature and maturation of its diverse progenitor populations are unexplored. The chromatin modifier DOT1L balances progenitor proliferation and differentiation, and conditional loss-of-function mice featured impaired hippocampus development. We applied single-cell RNA sequencing on DOT1L-mutant mice and explored cell trajectories in the E16.5 hippocampus. We resolved in our data five distinct neural stem cell populations with the developmental repertoire to specifically generate the cornu ammonis (CA) 1 field and the dentate gyrus (DG). Within the two developing CA1- and CA3-fields, we identified two distinct maturation states and we thus propose CA1- and CA3-differentiation along the radial axis. In the developing hippocampus, DOT1L is primarily involved in the proper development of CA3 and the DG, and it serves as a state-preserving epigenetic factor that orchestrates the expression of several important transcription factors that impact neuronal differentiation and maturation. Graphical Abstract The developing hippocampus contains distinct and spatially separated NSC populations that differ in expression of a specific set of firstly described marker genes. CA pyramidal neurons mature along the radial axis and pass through distinct maturation states. DOT1L preserves the dentate granule cell lineage in the developing hippocampus and limits maturation in the CA1- and CA3-fields development. DOT1L gates cell maturation as upstream regulator of transcription factor expression that confer instrumental roles in hippocampus development.