Epigenetic and 3D genome reprogramming during the aging of human hippocampus
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE299139 | GEO | 2025/06/10
REPOSITORIES: GEO
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Project description:Age-related cognitive decline in humans is associated with altered physiology of the hippocampus, a region critical for memory consolidation and spatial navigation. While changes in gene expression have been observed in aging brain cells, our understanding of the regulatory mechanisms underlying these changes and their connection to chromatin structure remains limited. To unravel these complexities, we have applied a comprehensive multi-omics approach, integrating single-nucleus gene expression, chromatin accessibility, DNA methylation, and 3D chromatin architecture data obtained from hippocampal tissues of 40 neurotypical human donors spanning the adult lifespan. We observed a striking loss of astrocytes during aging, including the subset of astrocytes that play a role in maintaining and regulating synaptic transmission. In individuals aged 50-75 years, microglia undergo a dramatic switch from a predominantly homeostatic state to an epigenetically primed inflammatory state that coincides with reprogramming of their DNA methylomes. In the aged cells, we detected erosion of the 3D genome architecture, where local chromatin domains are diminished, trans-chromosomal interactions are strengthened, and CTCF DNA binding is reduced. Importantly, age-related changes in chromatin folding have high correspondence with the aging transcriptome and epigenome in multiple cell types. Our data identifies age-associated changes in cell types/states and gene regulatory features that provide insight into the loss of synapses and cognitive decline that occurs in the human brain during aging.
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Project description:Age-related cognitive decline in humans is associated with altered physiology of the hippocampus, a region critical for memory consolidation and spatial navigation. While changes in gene expression have been observed in aging brain cells, our understanding of the regulatory mechanisms underlying these changes and their connection to chromatin structure remains limited. To unravel these complexities, we have applied a comprehensive multi-omics approach, integrating single-nucleus gene expression, chromatin accessibility, DNA methylation, and 3D chromatin architecture data obtained from the hippocampi of 40 neurotypical human donors spanning the adult lifespan. We observed a striking loss of astrocytes, oligodendrocyte precursor cells, and endothelial cells during aging. In particular, we observed a substantial decline in the subset of astrocytes that play a role in maintaining and regulating synaptic transmission. In addition, microglia undergo a dramatic switch from a predominantly homeostatic state to an epigenetically primed inflammatory state that coincides with reprogramming of their DNA methylomes and activation of endogenous retrotransposons. In the aged cells, we detected erosion of the 3D genome architecture, where local chromatin domains are diminished and trans-chromosomal interactions are strengthened. Importantly, age-related changes in chromatin folding have high correspondence with the transcriptome and epigenome in multiple cell types. Our data identifies age-associated changes in cell types/states and gene regulatory features that provide insight into the loss of synapses and cognitive decline that occurs in the human brain during aging.
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Project description:The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment counteracted age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is known to control neuronal functions. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the rejuvenating effects of environmental enrichment at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.
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