The histone modification H3K4me3 is altered at the ANK1 locus in Alzheimer's disease brain

Abstract

Several epigenome-wide association studies of DNA methylation have highlighted altered DNA methylation in the ANK1 gene in Alzheimer's disease (AD) brain samples. However, no study has specifically examined ANK1 histone modifications in the disease. We use chromatin immunoprecipitation-qPCR to quantify tri-methylation at histone 3 lysine 4 (H3K4me3) and 27 (H3K27me3) in the ANK1 gene in entorhinal cortex from donors with high (n = 59) or low (n = 29) Alzheimer's disease pathology. We demonstrate decreased levels of H3K4me3, a marker of active gene transcription, with no change in H3K27me3, a marker of inactive genes. H3K4me3 is negatively correlated with DNA methylation in specific regions of the ANK1 gene. Our study suggests that the ANK1 gene shows altered epigenetic marks indicative of reduced gene activation in Alzheimer's disease.

Lay abstract

Alzheimer's disease affects millions of people worldwide and numerous genetic association studies have been undertaken in the disease in recent years. The expression of genes can be altered by epigenetic processes, which include modifications to the DNA or histone proteins. Several studies have now reported increased DNA methylation in the ANK1 gene in Alzheimer's disease brain samples. However, to date no studies have explored histone modifications in this gene in the disease. Here, we show decreased levels of the H3K4me3 modification in regions of the ANK1 gene in the entorhinal cortex of Alzheimer's disease brain samples, which is a marker of active gene expression. This study further supports a role for epigenetic modifications in the ANK1 gene in Alzheimer's disease pathology.

Graphical abstract