Epigenetic studies in Alzheimer's disease and other conditions
It is well-established that DNA methylation plays an important role in controlling gene expression, which in turn can influence phenotypic variance and susceptibility to disease.
Dr. Ertekin-Taner's team hypothesizes that gene expression changes in the brain play a central role in susceptibility to Alzheimer's disease. The lab has significant publications in support of this hypothesis. The assumption is that identifying specific methylation changes that underlie these gene expression changes will lead to the identification of novel genes and pathways that are excellent drug targets for Alzheimer's disease.
The lab previously performed a gene expression genome-wide association study that assessed messenger RNA levels of approximately 24,000 transcripts in two brain regions — temporal cortex and cerebellum — for approximately 200 participants with Alzheimer's disease and approximately 200 more with other pathologies (non-Alzheimer's disease). A collection of CpG methylation data (methylome) for 92 of these same participants — 46 with Alzheimer's disease and 46 non-Alzheimer's disease — was established using DNA isolated from the temporal cortex to evaluate the influence of DNA methylation on gene expression in the brain.
Specifically, these data are being analyzed to:
- Determine differentially methylated regions, such as comparing participants with Alzheimer's disease versus those without Alzheimer's disease, to identify genes with altered methylation patterns in the brains of participants with Alzheimer's disease.
- Evaluate gene promoter regions for strong correlations with gene expression to identify genes that are under strong epigenetic control in the human brain that may be relevant to disease.
DNA methylation serves as a central epigenetic mechanism that governs gene regulation. It typically involves the addition of a methyl group to cytosine residues, most often at CpG sites. This modification influences chromatin structure and modulates gene expression by affecting the accessibility of regulatory regions.
Our lab has sought to provide comprehensive coverage of DNA methylation across the genome. We have identified approximately 2 million CpG methylation sites and generated a methylation atlas encompassing roughly 12,000 unique gene promoters, enabling robust correlation analyses between methylation patterns and gene expression levels.
The analysis has identified significant correlations between promoter CpG methylation and gene expression levels for genes that are differentially expressed between participants with and without Alzheimer's disease. This analysis provides a list of interesting genes for further study.
Dr. Ertekin-Taner's lab is generating and analyzing additional epigenetic data, including histone acetylation mark H3K27ac, ATACseq and RRBS-based methylation, from well-characterized and large-scale cohorts, as described under projects 2 and 4 of comparative gene expression studies in Alzheimer's disease and other conditions. These studies are expected to delineate the role of these epigenetic mechanisms in risk and other features of Alzheimer's disease.