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Peer-reviewedCC BY-NCCell Genomics

Single-cell profiling of DNA methylation in autism spectrum disorder prefrontal cortex reveals distinct regulatory and aging signatures

  • Katherine W. Eyring1
  • Cuining Liu2
  • Nasser Elhajjaoui3
  • Kevin Daniel Abuhanna3
  • Yi Zhang3
  • Zachary von Behren3
  • Min Jen Tsai3
  • Eleazar Eskin4
  • Daniel H. Geschwind
  • Chongyuan Luo5
5 affiliations
  1. 1Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
  2. 2Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
  3. 3Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
  4. 4Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
  5. 5Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected]
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Abstract

Autism spectrum disorder (ASD) is a common, genetically and clinically heterogeneous neurodevelopmental condition. Despite this diversity, studies of postmortem brain tissue have revealed convergent molecular changes across the cortex, including reduced synaptic function in subsets of excitatory and inhibitory neurons and increased glial reactivity. Whether these features are reflected in cell type-specific epigenetic signatures remains unknown. Here, we present the first single-cell analysis of DNA methylation (DNAm) coupled with transcriptomics in ASD. Using snmCT- seq, we profiled DNAm and gene expression from over 60,000 nuclei across 49 donors. We identified thousands of differentially methylated regions (DMRs) in ASD, enriched in promoters and regulatory elements active during both prenatal development and in adult cortex. ASD-related methylation changes were spatially localized but uncorrelated with gene expression, and were small in magnitude compared to robust age-associated effects. Age-DMRs were concentrated in excitatory neurons, enriched in known cognitive aging pathways, and revealed distinct roles for CG and non- CG methylation in the aging brain. Finally, we explored age-by-diagnosis interactions, identifying a reduction in inhibitory neuron abundance with age in ASD relative to controls, highlighting this area as a promising direction for future research. Highlights: We generate a single cell multi-omic dataset, jointly profiling DNA methylation and gene expression in autistic and neurotypical donorsWe identify thousands of cell type informed differentially methylated regions (DMRs) in ASD, particularly in excitatory neurons from superficial cortical lamina and microgliaASD-DMRs are enriched in promoters and known regulatory regions, but not strongly tied to gene expressionAge effects on DNA methylation are profound, cell type specific, and concentrated in excitatory neurons.

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Cite

BibTeXRIS
BibTeX
@article{eyring2026singlecell,
  title = {{Single-cell profiling of DNA methylation in autism spectrum disorder prefrontal cortex reveals distinct regulatory and aging signatures}},
  author = {Katherine W. Eyring and Cuining Liu and Nasser Elhajjaoui and Kevin Daniel Abuhanna and Yi Zhang and Zachary von Behren and Min Jen Tsai and Eleazar Eskin and Daniel H. Geschwind and Chongyuan Luo},
  journal = {Cell Genomics},
  year = {2026},
  month = jun,
  doi = {10.1016/j.xgen.2026.101278},
  url = {https://doi.org/10.1016/j.xgen.2026.101278},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Single-cell profiling of DNA methylation in autism spectrum disorder prefrontal cortex reveals distinct regulatory and aging signatures
AU  - Katherine W. Eyring
AU  - Cuining Liu
AU  - Nasser Elhajjaoui
AU  - Kevin Daniel Abuhanna
AU  - Yi Zhang
AU  - Zachary von Behren
AU  - Min Jen Tsai
AU  - Eleazar Eskin
AU  - Daniel H. Geschwind
AU  - Chongyuan Luo
PY  - 2026
DA  - 2026/06/19
JO  - Cell Genomics
DO  - 10.1016/j.xgen.2026.101278
UR  - https://doi.org/10.1016/j.xgen.2026.101278
AB  - Autism spectrum disorder (ASD) is a common, genetically and clinically heterogeneous neurodevelopmental condition. Despite this diversity, studies of postmortem brain tissue have revealed convergent molecular changes across the cortex, including reduced synaptic function in subsets of excitatory and inhibitory neurons and increased glial reactivity. Whether these features are reflected in cell type-specific epigenetic signatures remains unknown. Here, we present the first single-cell analysis of DNA methylation (DNAm) coupled with transcriptomics in ASD. Using snmCT- seq, we profiled DNAm and gene expression from over 60,000 nuclei across 49 donors. We identified thousands of differentially methylated regions (DMRs) in ASD, enriched in promoters and regulatory elements active during both prenatal development and in adult cortex. ASD-related methylation changes were spatially localized but uncorrelated with gene expression, and were small in magnitude compared to robust age-associated effects. Age-DMRs were concentrated in excitatory neurons, enriched in known cognitive aging pathways, and revealed distinct roles for CG and non- CG methylation in the aging brain. Finally, we explored age-by-diagnosis interactions, identifying a reduction in inhibitory neuron abundance with age in ASD relative to controls, highlighting this area as a promising direction for future research. Highlights: We generate a single cell multi-omic dataset, jointly profiling DNA methylation and gene expression in autistic and neurotypical donorsWe identify thousands of cell type informed differentially methylated regions (DMRs) in ASD, particularly in excitatory neurons from superficial cortical lamina and microgliaASD-DMRs are enriched in promoters and known regulatory regions, but not strongly tied to gene expressionAge effects on DNA methylation are profound, cell type specific, and concentrated in excitatory neurons.
SN  - 2666-979X
ER  -