Transposable Element-Mediated Epigenomic Remodeling Drives Erythropoietin-Induced Neurogenesis in the Adult Hippocampus

Understanding the molecular mechanisms by which erythropoietin (EPO) is associated with neurogenesis is essential to harness its therapeutic potential for cognitive and neuropsychiatric disorders. Here, we employed single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), combined with single-nucleus RNA sequencing (snRNA-seq), to map the epigenomic and transcriptional landscapes of adult mouse hippocampus under recombinant human EPO (rhEPO) treatment. We discovered significant lineage-specific remodelling of chromatin accessibility predominantly in newly formed pyramidal neurons, highlighting a robust EPO-driven neurogenic response. Notably, transposable elements (TEs), particularly ancient LINEs and SINEs, emerged as critical cis-regulatory elements extensively bound by key neurogenic transcription factors such as NEUROD1/2, FOXG1, and ASCL1. Integrative analyses revealed that these TE-derived regulatory elements orchestrate gene networks involved in neuronal differentiation, synaptogenesis, and synaptic plasticity. Our findings highlight a previously unrecognised role of TEs as dynamic regulators in EPO-induced hippocampal re-wiring of gene regulatory networks associated with neurogenesis, establishing a valuable epigenomic resource for advancing therapeutic strategies targeting cognitive deficits and neurodegenerative conditions.