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Histone Acetylome-Wide Study Finds Epigenetic Differences in Alzheimer's Disease

NEW YORK (GenomeWeb) – Researchers have uncovered widespread dysregulation of histone acetylation among individuals with Alzheimer's disease.

Alzheimer's disease (AD) affects more than 26 million people around the world, and while variants in various genes have been linked to early-onset familial AD and late-onset sporadic AD, the epigenome is also suspected to have a role in disease development.

A University of Exeter-led team of researchers characterized lysine H3K27 acetylation, a marker of active enhancers and promoters, in brain tissue from people with and without AD. As they reported in Nature Neuroscience today, the researchers found numerous differentially acetylated peaks, including ones near the regulatory regions of genes involved in amyloid-β (Aβ) and tau pathology.

"Our study provides compelling evidence for widespread changes in histone acetylation in Alzheimer's disease," co-senior author Jonathan Mill from the University of Exeter Medical School said in a statement. "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."

The researchers relied on chromatin immunoprecipitation-sequencing to quantify the levels of H3K27ac across 47 entorhinal cortex samples, a brain region affected early in the development of AD. These samples were collected postmortem from 24 AD patients and 23 age-matched controls, all from individuals of Western European ancestry.

Overall, the researchers generated a mean 30 million sequencing reads per sample, which enabled them to identify more than 180,000 H3K27ac peaks, which they then validated in two other datasets. Of these peaks, 4,162 were differentially acetylated between AD cases and controls.

They annotated these differentially acetylated peaks — both hyperacetylated and hypoacetylated — to 4,039 genes. The most significant hyperacetylated peak was annotated to both SOX1 and TEX29, while the most significant hypoacetylated peak was annotated to ZNF680.

A number of these peaks could also be traced to regions near genes involved in AD-related pathology. For instance, one hyperacetylated peak is near the MAPT gene, which encodes the microtubule-associated protein tau. Tau, the researchers noted, is thought to have a key role in AD in the development of its hallmark neurofibrillary tangles.

Similarly, a hypoacetylated peak was found downstream of the amyloid precursor protein (APP) gene, which encodes a precursor molecule to Aβ, the main part of the disease's amyloid plaques.

They likewise noted hyperacetylation near both PSEN1 and PSEN2, which encode parts of the gamma secretase complex and help generated Aβ from APP and have been linked to early-onset familial AD.

Using a hypergeometric test, the researchers confirmed that this AD-associated differential acetylation was associated with APP, PSEN1, and PSEN2, which are all linked to familial AD, as well as to the MAPT locus, and all four combined. As their the cases in their cohort had sporadic AD, this suggested to the researchers that similar processes might be involved in the development of both the familial and sporadic forms of the disease.

In a separate set of 95 entorhinal cortex samples from cases and controls, the researchers found that some genes located near top-ranked differentially acetylated peaks — including CR1, GPR22, KMO, PIM3, PSEN1, and RGCC — also exhibited transcriptional variation.

"Changes influencing the activity of many genes were found to be robustly associated with the pathological hallmarks of Alzheimer's disease," first author Sarah Marzi from King's College London and Queen Mary University of London said in a statement. "Interestingly, our results suggest there are common mechanisms both hereditary and isolated forms of this terrible illness."

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