Yonatan Shapira, Florian Noack, Silvia Vangelisti, Faye Chong, Aviezer Lifshitz et al.
During cortical development, neural stem cells (NSCs) combine self-renewal with the sequential production of different subtypes of projection neurons as well as glia cells. How the NSC epigenome accommodates this over time remains unresolved. Here, we address this gap by multimodal epigenomic profiling of mouse cortical development across six time points and five embryonic days. Single-cell gene expression and temporal modeling reveal that NSC self-renewal is not homeostatic, showing progressively stronger astrocytic preference over time. Chromosome accessibility, DNA methylation, and Hi-C show that this process involves major reorganization of the NSC epigenome. A model combining transcription factor motif affinities with epigenetic features, as well as integration of the results with a reporter assay in vivo, show that activation of the NSC neuronal fate regulatory program may be affected by a changing epigenome. Collectively, our findings uncover temporal epigenomic reprogramming that underlies the evolving differentiation potential of NSCs, providing insights into the intrinsic and extrinsic mechanisms that pattern cortical lineages.
Yonatan Shapira, Florian Noack, Silvia Vangelisti, Faye Chong, Aviezer Lifshitz, Amos Tanay, Boyan Bonev. Neural stem cell epigenomes and fate bias are temporally coordinated during mouse cortical development. 2026-04-22. https://doi.org/10.1101/gad.353090.125
A shared 266-bp episomal MPRA library containing putative cortical cis-regulatory elements and GC-matched scrambled controls was electroporated in utero into mouse somatosensory cortex at E12-E16. Tbr2+ intermediate progenitors were FACS-isolated 24 hours later and profiled as DNA input and RNA output across collection days E13-E17.
A shared 266-bp episomal MPRA library containing putative cortical cis-regulatory elements and GC-matched scrambled controls was electroporated in utero into mouse somatosensory cortex at E12-E16. Pax6+ neural stem cells were FACS-isolated 24 hours later and profiled as DNA input and RNA output across collection days E13-E17.
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Download all 4 files (ZIP)GSE292321.geo.txtGSE292321_family.soft.gzGSE292321_Shapira2025_devMPRA.tsv.gzREADME.txt