Rare genetic variation at transcription factor binding site modulates local DNA methylation profiles

Recently, it has been proposed that local DNA methylation profiles might be dictated by cis-regulatory DNA sequences that mainly operate via DNA-binding factors. Combining blood genome-wide DNA methylation profiles (Illumina Infinium MethylationEPIC BeadChiP), whole genome sequencing-derived single nucleotide variants (SNVs) along with predicted transcription factor binding site (TFBS), we were able to observe that rare regulatory variants, i.e, SNVs that disrupt TFBSs, are associated with DNA methylation at both local and, to a lesser extent, broader locations. Interestingly, we also observed that this directed DNA methylation can have consequences on genome regulation by altering expression levels of nearby genes. About 500ng of genomic DNA was bisulfite-converted and analyzed for genome-wide methylation patterns using the Infinium MethylationEPIC BeadChiP platform at the New York Genome Center (New York, USA), according the manufacturer's recommendation for Illumina Infinium Assay. All samples are from individuals with congenital heart defects. Contributor: Pediatric Cardiac Genomics Consortium (PCGC)