Epigenetic Studies in AD and Other Conditions
It is well-established that DNA methylation plays an important role in control of 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 for Alzheimer's disease (AD); the lab has significant publications in support of this hypothesis. The assumption is that identification of specific methylation changes that underlie these gene expression changes will lead to identifying novel genes and pathways that are excellent drug targets for AD.
The lab previously performed a gene expression genome-wide association study (GWAS) that assessed mRNA levels of approximately 24,000 transcripts in two brain regions (temporal cortex and cerebellum) for approximately 200 participants with AD and approximately 200 more with other pathologies (non-AD). A collection of CpG methylation data (methylome) for 92 of these same participants (46 AD and 46 non-AD) was established using DNA isolated from the temporal cortex to evaluate the influence of DNA methylation on gene expression in the brain.
Specifically, the data is being analyzed to:
- Determine differentially methylated regions, such as comparing participants with AD versus those without AD, to identify genes with altered methylation patterns in the brains of participants with AD
- 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
The lab has collected DNA methylation data for approximately 2 million CpGs and generated summary methylation phenotypes for approximately 12,000 unique gene promoters for correlation analysis with 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 AD and provides a list of interesting genes for further study.
Currently, 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 Comparative Gene Expression Studies in AD and Other Conditions projects 2 and 4. These studies are expected to delineate the role of these epigenetic mechanisms in risk and other features of AD.