In our quest for the fountain of youth, we often find ourselves attracted to anything that will fight off the signs of aging. But now, the first genome-wide analysis of a specific histone modification in the brains of human patients affected by Alzheimer’s disease (AD) demonstrates that we should embrace the epigenetic changes that come with healthy aging since they can help protect us from disease development.
The H4K16ac modification not only associates with active enhancers and promoters, but also with senescence in mammalian cell culture and aging in model organisms. This intriguing age-related association prompted the labs of labs of Shelley Berger, Nancy Bonini, and Brad Johnson from the University of Pennsylvania to investigate the role of H4K16ac in AD. To tackle this feat, the talented team employed H4K16ac ChIP-seq of a brain region affected early in AD development, the lateral temporal lobe, and compared their results with younger (~52 years old) and elderly (~62 years old) cognitively normal control samples. Notably, the group quantified neurons by flow cytometry to mask ChIP-seq peaks associated with neuronal loss.
Here’s what they discovered:
- While all groupings exhibit losses and gains of H4K16ac peaks that correlate with gene expression, H4K16ac levels preferentially decrease in AD patients and increase in older patient samples
- Intriguingly, the gains observed during normal aging negatively correlate with AD losses, suggesting that AD represents a deregulated aging process
- Transcription factor motif analysis revealed an enrichment for the HIC ZBTB Transcriptional Repressor 1 (HIC1) binding motif at regions of H4K16ac gained during aging and lost during AD
- There are 3 types of H4K16ac changes that occur with AD: age-regulated, age-deregulated, and disease-specific
- The differential H4K16ac peaks associated with AD are enriched for expression quantitative trait loci (eQTLs) and SNPs identified by AD genome-wide association studies (GWAS)
First author Raffaella Nativio shares, “These analyses point to a new model of Alzheimer’s disease. Specifically it appears that AD is not simply an advanced state of normal aging, but rather dysregulated aging that may induce disease-specific changes to the structure of chromatin”. Taken together, these findings demonstrate that not all age related epigenetic changes should be thought of as undesirable.
Take a detour from the fountain of youth over at Nature Neuroscience, March 2018