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Peer-reviewedCC BY 4.0Cells

Cross-Species and Cell-Type-Specific H3K27ac Dynamics Link Brain Aging to Alzheimer’s Disease Genes

  • Ching-Thong Choo1,2
  • Zhen-Kai Ngian1
  • Chin-Tong Ong1,2
  1. 1Temasek Life Sciences Laboratory, Singapore 117604, Singapore
  2. 2Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
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Abstract

Active H3K27ac marks are dynamically remodelled during brain aging, but their cell-type-specific regulatory roles remain unclear. We integrated genome-wide H3K27ac profiles and transcriptomes from aging Drosophila heads, mouse NeuN+ forebrain neurons, and human NeuN+/NeuN− frontal cortex cells. In Drosophila, age-gained differential (Δ) H3K4me1 and H3K27ac peaks were associated with RNA processing and immune response genes, respectively, suggesting distinct regulatory programs. Despite limited biological replicates, mouse analyses revealed a strong association between promoter-associated ΔH3K27ac and synaptic gene expression in young neurons. Age-related gene-body H3K27ac loss coincided with increased expression of genes involved in GTPase signalling and vesicular transport. In humans (n = 29), NeuN− cells exhibited more age-associated ΔH3K27ac alterations than NeuN+ cells. Genes associated with age-gained peaks were enriched for gliogenesis and amyloid precursor protein metabolic processes, while age-related transcriptional changes associated positively with super-enhancer activity. Comparison with pan-tissue aging signatures revealed shared and cell-type-specific age-related ΔH3K27ac patterns in NeuN+ and NeuN− cells. Integrative analyses showed that age-gained ΔH3K27ac peaks in NeuN− cells overlapped with AD-associated ΔH3K27ac peaks, differentially expressed AD genes, and AD GWAS-linked variants, including those mapped to BIN1 and CR1. These findings highlight extensive H3K27ac remodelling in aging NeuN− cells and its convergence with AD-associated molecular alterations.

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Cite

BibTeXRIS
BibTeX
@article{choo2026crossspecies,
  title = {{Cross-Species and Cell-Type-Specific H3K27ac Dynamics Link Brain Aging to Alzheimer’s Disease Genes}},
  author = {Ching-Thong Choo and Zhen-Kai Ngian and Chin-Tong Ong},
  journal = {Cells},
  year = {2026},
  month = nov,
  doi = {10.3390/cells15212007},
  url = {https://www.mdpi.com/2073-4409/15/21/2007},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Cross-Species and Cell-Type-Specific H3K27ac Dynamics Link Brain Aging to Alzheimer’s Disease Genes
AU  - Ching-Thong Choo
AU  - Zhen-Kai Ngian
AU  - Chin-Tong Ong
PY  - 2026
DA  - 2026/11/04
JO  - Cells
DO  - 10.3390/cells15212007
UR  - https://www.mdpi.com/2073-4409/15/21/2007
AB  - Active H3K27ac marks are dynamically remodelled during brain aging, but their cell-type-specific regulatory roles remain unclear. We integrated genome-wide H3K27ac profiles and transcriptomes from aging Drosophila heads, mouse NeuN+ forebrain neurons, and human NeuN+/NeuN− frontal cortex cells. In Drosophila, age-gained differential (Δ) H3K4me1 and H3K27ac peaks were associated with RNA processing and immune response genes, respectively, suggesting distinct regulatory programs. Despite limited biological replicates, mouse analyses revealed a strong association between promoter-associated ΔH3K27ac and synaptic gene expression in young neurons. Age-related gene-body H3K27ac loss coincided with increased expression of genes involved in GTPase signalling and vesicular transport. In humans (n = 29), NeuN− cells exhibited more age-associated ΔH3K27ac alterations than NeuN+ cells. Genes associated with age-gained peaks were enriched for gliogenesis and amyloid precursor protein metabolic processes, while age-related transcriptional changes associated positively with super-enhancer activity. Comparison with pan-tissue aging signatures revealed shared and cell-type-specific age-related ΔH3K27ac patterns in NeuN+ and NeuN− cells. Integrative analyses showed that age-gained ΔH3K27ac peaks in NeuN− cells overlapped with AD-associated ΔH3K27ac peaks, differentially expressed AD genes, and AD GWAS-linked variants, including those mapped to BIN1 and CR1. These findings highlight extensive H3K27ac remodelling in aging NeuN− cells and its convergence with AD-associated molecular alterations.
SN  - 2073-4409
ER  -