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PLoS One. 2017 Sep 28;12(9):e0180903. doi: 10.1371/journal.pone.0180903. eCollection 2017.

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

Author information

1
Department of Biomedical Engineering, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
2
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
3
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
4
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.
5
Division of Allergy and Clinical Immunology Department of Medicine, The Johns Hopkins University, Baltimore, MD, United States of America.
6
Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
7
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
8
Department of Epidemiology, Human Genetics and Environmental Sciences, Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, United States of America.
9
Department of Internal Medicine, Division of Cardiology, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
10
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.

Abstract

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.

PMID:
28957329
PMCID:
PMC5619705
DOI:
10.1371/journal.pone.0180903
[Indexed for MEDLINE]
Free PMC Article

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