371: Glial epigenomic dysregulation and genetic risk in tauopathies

Han et al., Nature Communications - This study uses paired single-nucleus chromatin accessibility and gene expression profiling across Alzheimer’s disease, Pick’s disease and progressive supranuclear palsy to map disease-dynamic cis-regulatory elements (CREs). Dynamic chromatin changes concentrate genetic risk in glial cell states and co-regulated regulatory modules. Integrating GWAS, sn-eQTLs and MPRA validates functional noncoding variants that tune lysosomal, lipid and vesicular pathways. Experimental CRISPRa and histology support a stress-inducible SOX10-driven glial program linked to resilience. Key terms: snATAC-seq, tauopathies, microglia, chromatin accessibility, SOX10.

Study Highlights:
The authors profiled matched snATAC-seq and snRNA-seq from three brain regions across AD, PiD and PSP and defined cell-type-specific CREs and 50 subclusters. Disease-dynamic peaks concentrated in glia and disproportionately capture GWAS heritability, with PiD-linked mg.C4 microglia and PSP-linked ast.C1 astrocytes identified as risk-associated states. MPRA in microglial models and sn-eQTL integration validated functional regulatory variants that converge on MEF2C/SOX10 and SNARE-centered modules affecting lysosomal, sphingolipid and trafficking pathways. CRISPRa induction of SOX10 in iPSC-derived microglia under synaptosome stress recapitulated mg.C4 programs, and RNAscope/IHC confirmed SOX10+/PLP1+ glial states in human tissue.

Conclusion:
Dynamic, disease-context-specific chromatin remodeling in glia concentrates genetic risk into co-regulated regulatory modules that modulate lysosomal, lipid and vesicular pathways; these modules nominate SOX10-, MEF2- and SNARE-centered circuits as candidate modulators of glial resilience across tauopathies.

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Article title:
Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states

First author:
Han

Journal:
Nature Communications

DOI:
10.1038/s41467-026-73007-1

Reference:
Han, X., Rosenberg, G.M., Kisling, V.M. et al. Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73007-1

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-19.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript portions describing glial states mg.C4 microglia and ast.C1 astrocytes, regulatory networks (MEF2C/MEF2D), SOX10's role and ectopic expression, MPRA validation, CRISPRaSOX10 experiments, dynamic CREs and heritability findings, and study limitations.
- transcript topics: Glial states mg.C4 microglia and ast.C1 astrocytes across tauopathies; MEF2C/MEF2D regulatory modules linking to lysosomal and phagocytic pathways; SOX10 as a stress-responsive regulator and ectopic expression in glia; MPRA validation of regulatory variants in microglia (frVars); CRISPRa SOX10 activation in hiPSC-derived microglia and recapitulation of mg.C4 programs; Dynamic CREs and GWAS heritability enrichment across disorders

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Number of nuclei and samples studied: 682,667 high-quality nuclei from 41 brains
- Regions analyzed in main comparisons: Precentral Gyrus (PreCG) and insula; calcarine cortex excluded due to variability
- Identification of disease-associated glial states mg.C4 microglia and ast.C1 astrocytes
- Dynamic CREs enrich disease heritability, with PiD mg.C4 driving FTD heritability and PSP ast.C1 contributing PSP heritability
- MEF2C/MEF2D regulatory modules link to lysosomal and phagocytic pathways in mg.C4 microglia
- SOX10 is enriched/activated in mg.C4 and ast.C1 and acts as a stress-responsive regulator

QC result: Pass.