Single-nucleus epigenomic profiling of the adult human central nervous system unveils epigenetic memory of developmental programs

Kabbe, Mukund; Agirre, Eneritz; Carlström, Karl E.; Dumral, Özge; Lor, Yuk Kit; Pohl, Fabio Baldivia; Ruffin, Nicolas; van Bruggen, David; Meijer, Mandy; Seeker, Luise A.; Bestard-Cuche, Nadine; Lederer, Alex R.; Zhang, Jilin; Ahola, Virpi; Goldman, Steven A.; Edström, Erik; Arvidsson, Lisa; Moreira, Tiago Holm; Bartosovic, Marek; Jagodic, Maja; Williams, Anna; Castelo-Branco, Gonçalo

Single-nucleus epigenomic profiling of the adult human central nervous system unveils epigenetic memory of developmental programs

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Item Type:	Article
Title:	Single-nucleus epigenomic profiling of the adult human central nervous system unveils epigenetic memory of developmental programs
Creators Name:	Kabbe, Mukund, Agirre, Eneritz, Carlström, Karl E., Dumral, Özge, Lor, Yuk Kit, Pohl, Fabio Baldivia, Ruffin, Nicolas, van Bruggen, David, Meijer, Mandy, Seeker, Luise A., Bestard-Cuche, Nadine, Lederer, Alex R., Zhang, Jilin, Ahola, Virpi, Goldman, Steven A., Edström, Erik, Arvidsson, Lisa, Moreira, Tiago Holm, Bartosovic, Marek, Jagodic, Maja, Williams, Anna and Castelo-Branco, Gonçalo
Abstract:	Neural cells in the adult human central nervous system (CNS) display extensive transcriptional heterogeneity. How different layers of epigenetic regulation underpin this heterogeneity is poorly understood. Here we profile, at the single-nuclei epigenomic level, distinct regions of the adult human CNS, for chromatin accessibility and simultaneously for the histone modifications H3K27me3 and H3K27ac. We unveil a putative SOX10 enhancer and primed chromatin signatures at HOX loci in spinal-cord-derived human oligodendroglia (OLG) and astrocytes, but not microglia. These signatures in adult OLG were reminiscent of developmental profiles but were decoupled from robust gene expression. Moreover, using high-resolution Micro-C, we show that induced pluripotent stem-cell-derived human OLGs exhibit a HOX chromatin architecture compatible with the primed chromatin in adult OLGs, bearing a strong resemblance not only to OLG developmental architecture but also to high-grade pontine gliomas. Thus, epigenetic memory from developmental states in adult OLG not only enables them to promptly transcribe Hox family genes during regeneration but also makes them susceptible to gliomagenesis.
Source:	Nature Neuroscience
ISSN:	1097-6256
Publisher:	Nature Publishing Group
Date:	19 March 2026
Official Publication:	https://doi.org/10.1038/s41593-026-02208-0
PubMed:	View item in PubMed
Related to:	URL URL Type https://ega-archive.org/datasets/EGAD50000000410 External Dataset https://ega-archive.org/datasets/EGAD50000001542 External Dataset https://ega-archive.org/datasets/EGAD50000001535 External Dataset https://cns-nanocuttag-atac.cells.ucsc.edu/ External Dataset https://ki.se/en/mbb/oligointernode External Dataset https://github.com/mkabbe/snATACnanoCT_AdultHumanCNS Software

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