Recapitulation of juvenile-like histone landscape in aged neurons

The greatest risk factor for dementia is increasing age. During healthy aging the activity of neurons underlie a range of cognitive trajectories from unimpaired to significant decline. The epigenome is the interface between our genes and the environment and comprises a highly interactive network of chemical moieties (including histone modifications). The epigenetic signature of each cell type is unique, yet few studies have examined the epigenome in aged neurons. We characterised H3K27ac and H3K4me3 histone modifications using ChIP-seq in forebrain neurons from 3, 6, 12, and 24 month (m) old C57/Bl6 mice (n=5/timepoint). H3K27ac and H3K4me3 marking was enriched at promoters and enhancers in neurons from juvenile (3m) and aged (24m) mice compared to neurons from adult mice (6m&12m). Gene ontology (GO) analysis annotated to synaptic and core molecular processes across life. Developmental GOs were unique to juvenile neurons, while annotations that were unique to adult neurons included axonal transport, protein folding and membrane depolarisation. GO pathways that were unique to aged neurons included apoptosis, autophagy and RNA processing. Surprisingly, we detected a partial recapitulation of a juvenile-like histone landscape in aged neurons; >25% of H3K27ac and H3K4me3 differentially marked sites were shared between juvenile and aged neurons and >87% of these shared sites were consistently enriched in both juvenile and aged neurons. This work reveals epigenetic alterations that impact neurons across aging. Our long-term goal is to identify the epigenetic changes that drive neuronal dynamics in healthy aging and dysfunction in dementia to discover direct and indirect therapeutic targets.