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bioRxiv · 10.1101/2025.10.13.682070

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

Cakir, U.·Fritz, M.·Butt, U. J.·Kawaguchi, R.·Geschwind, D.·Nave, K.-A.·Ehrenreich, H.·Singh, M.
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Abstract

Understanding the molecular mechanisms by which erythropoietin (EPO) acts as neurotrophic factor that enhances hippocampal function and learning is essential to harness its therapeutic potential. Here, we employ single-nucleus ATAC-seq and RNA-seq to map the epigenomic and transcriptional landscapes of adult mouse hippocampus under recombinant human EPO (rhEPO) treatment. We discover significant lineage-specific chromatin remodeling predominantly in newly formed and immature excitatory neurons, highlighting a robust EPO-driven neurogenic response as the first direct evidence that an extrinsic factor can induce adult hippocampal neurogenesis. Notably, many EPO-induced accessible regions overlap ancient transposable elements, particularly ancient LINEs and SINEs, that are bound by key neurogenic transcription factors such as NEUROD1/2, NEUROG2, FOXG1, and ASCL1 and are linked to nearby genes governing neuronal differentiation and synaptic plasticity. Our findings uncover a previously unrecognized transposon-mediated mechanism underlying EPO-induced neurogenesis, highlighting an underappreciated role for TE-derived sequences in this process, and establish a publicly available single-nucleus multiomic atlas as a resource for understanding cell-type-specific gene regulation and neuroplasticity in the adult brain.

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Cakir, U., Fritz, M., Butt, U. J., Kawaguchi, R., Geschwind, D., Nave, K.-A., Ehrenreich, H., Singh, M.. 2025-10-14. Transposable Element-Mediated Epigenomic Remodeling Drives Erythropoietin-Induced Neurogenesis in the Adult Hippocampus. https://doi.org/10.1101/2025.10.13.682070

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