A single-nucleus regulatory atlas links transposable elements to adult hippocampal neurogenesis

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SUMMARY Adult hippocampal neurogenesis can be enhanced or even triggered by extrinsic stimuli, but the lineage-specific regulatory changes that accompany a stimulated neurogenic response remain undefined. We used recombinant human erythropoietin (rhEPO), a defined influencing factor that enriches newly formed pyramidal neurons by ∼2 fold in this paradigm 1 , to profile ∼35,000 nuclei by single-nucleus ATAC sequencing (snATAC-seq) from rhEPO- and placebo-treated adult mouse hippocampi and to integrate them with matched single-nucleus RNA sequencing (snRNA-seq) of ∼120,000 nuclei. Thirty-five accessibility-defined clusters resolved 11 major lineages. Of 39,404 differentially accessible regions (DARs), more than half arose in pyramidal neurons, whereas dentate gyrus granule neurons and interneurons showed predominantly reduced accessibility; within the pyramidal lineage, remodelling was predominant in newly-formed rather than mature neurons. About 20% of hippocampal candidate cis-regulatory elements (cCREs) overlapped transposable elements (TEs) at baseline, rising to about 50% among regions that gained accessibility upon stimulation, and multiple families were significantly bound above the expected threshold by neurogenic transcription factors, whereby the many neighbouring genes have established roles for neuronal differentiation and synapse formation. These data define TE-derived sequences as candidate components of stimulus-responsive neurogenic regulatory networks and provide a cell-type-specific chromatin resource for the adult hippocampus at single-nucleus resolution. HIGHLIGHTS Single-nucleus atlas resolves chromatin accessibility across hippocampal lineages More than half of EPO-responsive accessible regions arise in pyramidal neurons Newly formed pyramidal neurons show the strongest chromatin remodelling TEs bound by neurogenic TFs serve as candidate cis-regulatory element for neurogenesis genes IN BRIEF Cakir et al. provide a lineage-resolved chromatin accessibility atlas of the adult mouse hippocampus under a controlled pro-neurogenic stimulus. Chromatin responses are unevenly distributed across lineages and concentrated in newly formed pyramidal neurons, and a substantial fraction of stimulus-responsive regions is derived from specific retrotransposons bound by neurogenic transcription factors.

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