When it comes to the complex disorders associated with aging, our knowledge could always use some enhancement. Thankfully, a new histone acetylome-wide association study (HAWAS) of H3K27ac establishes that this mark of active enhancers can also enhance our knowledge of Alzheimer’s disease (AD).
The role of histone acetylation in healthy aging and AD has begun to emerge, and the labs of Jonathan Mill and Leonard Schalkwyk (King’s College London, University of Exeter, and University of Essex, UK) sought to build on their past DNA methylation studies. In their latest efforts, the team utilized H3K27ac ChIP-seq to examine post-mortem brains (entorhinal cortex) from 24 patients with advanced AD neuropathology and 23 age-matched control patients with minimal neuropathology.
Here’s what they discovered:
- Of the 182,065 H3K27ac peaks called, 4,162 differentiate patients with AD from matched controls
- Analyses uncovered a significant enrichment for hypoacetylation (2,687 hypoacetylated peaks and 1,475 hyperacetylated peaks)
- The differential H3K27ac peaks map to the regulatory regions of genes previously implicated in AD, including those involved in tau and amyloid neuropathology
- The AD peaks associate with known Alzheimer’s disease GWAS hits, functions related to neuropathology, and variable expression of select nearby genes
- However, when compared with the differential DNA modifications (5mC and 5hmC) previously identified in the same samples, the team observed unique distributions with some overlap
First author Sarah Marzi shares, “Changes influencing the activity of many genes were found to be robustly associated with the pathological hallmarks of Alzheimer’s disease. Interestingly, our results suggest there are common mechanisms both hereditary and isolated forms of this terrible illness.”
Co-Senior author Leonard Schalkwyk adds, “Alzheimer’s affects millions of lives and has been extensively studied but we still haven’t got to the bottom of why and how it happens. This is our second large-scale study on the chromosomes of the most-affected parts of the brain, to find different epigenetic differences in how genes are expressed in Alzheimer’s disease compared to an unaffected brain. Thisis helping to tie different strands of our understanding of the disease together.”
Co-Senior author Jonathan Mill concludes “Our study provides compelling evidence for widespread changes in histone acetylation in Alzheimer’s disease. Although more work is needed to explore whether altered histone acetylation is a cause or a result of the condition, it is interesting that drugs modifying histone acetylation are among the most promising new treatments for Alzheimer’s disease.”