Journal Article

Uncovering the DNA methylation landscape in key regulatory regions within the FADS cluster

Langefeld, Carl D., Rahbar, Elaheh, Howard, Timothy D., Seeds, Michael C., Hixson, James E., Chilton, Floyd H., Mathias, Rasika, Hawkins, Gregory A., Ruczinski, Ingo, Herrington, David M., Ainsworth, Hannah C., Sergeant, Susan

2017

Overview

Genetic variants near and within the fatty acid desaturase (FADS) cluster are associated with polyunsaturated fatty acid (PUFA) biosynthesis, levels of several disease biomarkers and risk of human disease. However, determining the functional mechanisms by which these genetic variants impact PUFA levels remains a challenge. Utilizing an Illumina 450K array, we previously reported strong allele-specific methylation (ASM) associations (p = 2.69×10-29) between a single nucleotide polymorphism (SNP) rs174537 and DNA methylation of CpG sites located in the putative enhancer region between FADS1 and FADS2, in human liver tissue. However, this array only featured 20 CpG sites within this 12kb region. To better understand the methylation landscape within this region, we conducted bisulfite sequencing of the region between FADS1 and FADS2. Liver tissues from 50 male subjects (27 European Americans, 23 African Americans) were obtained from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, and used to ascertain the genotype at rs174537 and methylation status across the region of interest. Associations between rs174537 genotype and methylation status of 136 CpG sites were determined. Age-adjusted linear regressions were used to assess ASM associations with rs174537 genotype. The majority of CpG sites (117 out of 136, 86%) exhibited high levels of methylation with the greatest variability observed at three key regulatory regions-the promoter regions for FADS1 and FADS2 and a putative enhancer site between the two genes. Eight CpG sites within the putative enhancer region displayed significant (FDR p <0.05) ASM associations with rs174537. These data support the concept that both genetic and epigenetic factors regulate PUFA biosynthesis, and raise fundamental questions as to how genetic variants such as rs174537 impact DNA methylation in distant regulatory regions, and ultimately the capacity of tissues to synthesize PUFAs.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Arteriosclerosis / Atherosclerosis / Biology and life sciences / Biomarkers / Biosynthesis / Bisulfite / Black or African American - genetics / Cardiovascular disease / Chronology / Clusters / CpG islands / CpG Islands - genetics / Delta-5 Fatty Acid Desaturase / Demography / Deoxyribonucleic acid / Desaturase / DNA / DNA methylation / DNA Methylation - genetics / Epigenetics / Fatty Acid Desaturases - genetics / Fatty acids / Fish oils / Gene expression / Genetic aspects / Genetic variance / Genomics / Genotype / Health risks / Health sciences / Humans / Internal medicine / Liver / Meta-analysis / Metabolic syndrome / Metabolites / Methylation / Minority & ethnic groups / Multigene Family / People and Places / Physical Sciences / Physiological aspects / Polymorphism / Polymorphism, Single Nucleotide - genetics / Polyunsaturated fatty acids / Precision medicine / Preschool children / Prostate / Public health / Regulatory sequences / Regulatory Sequences, Nucleic Acid - genetics / Research and Analysis Methods / Risk factors / Sequence Analysis, DNA / Signal transduction / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Studies / Tissues / Unsaturated fatty acids / White People - genetics / Youth