Dysregulation of Histone Acetylation in Alzheimer’s Disease
In Alzheimer’s disease (AD) pathology, neuronal histone acetylation is reduced at memory-related genes . Nativio et al specifically researched H4K16ac, a regulator of chromatin compaction, because it plays an important role in cellular aging and senescence . By comparing the genome-wide profiles of H4K16ac in brain tissues from AD patients and controls the authors hope to determine the role of H4K16ac in brain aging and AD progression.
The team performed H4K16ac ChIP-seq in the lateral temporal lobe of postmortem brain tissues from three groups of people: old cognitively normal (Old, mean age=68), old with AD (AD, mean age=68) and young cognitively normal (Young, mean age=52). Overall, the number of H4K16ac peaks increased more in Old than AD samples compared to Young controls. Furthermore, while Old individuals had a higher accumulation of H4K16ac at transcription start sites compared to Young individuals, individuals with AD had lower levels of H4K16ac than young at these sites.
To identify the regions of the genome associated with H4K16ac peaks, Nativio et al overlapped the peak locations with genetic variants known to affect mRNA transcript expression levels. H4K16ac peaks were enriched at genetic variants located in regulatory elements of genes associated with AD pathology. This gives evidence to the concept that chromatin structure and AD pathology are related.
In summary, the changes in H4K16ac peaks at transcription start sites seen in AD are inversely correlated with H4K16ac changes related to normal aging. H4K16ac peak locations overlap with expression regulatory elements involved in AD pathology. This study shows that histone acetylation may play a role in AD pathology by changing gene expression levels in neurons and supports the theory that AD is a dysregulation of aging, not exacerbated aging in the brain.
- Nativio et al., “Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease.,” Nat. Neurosci., vol. 21, no. 4, pp. 497–505, Apr. 2018.
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- W. Dang et al., “Histone H4 lysine 16 acetylation regulates cellular lifespan.,” Nature, vol. 459, no. 7248, pp. 802–807, Jun. 2009.