title: Methylomics of gene expression in human monocytes.
abstract: DNA methylation is one of several epigenetic mechanisms that contribute to the regulation of gene expression; however, the extent to which methylation of CpG dinucleotides correlates with gene expression at the genome-wide level is still largely unknown. Using purified primary monocytes from subjects in a large community-based cohort (n = 1264), we characterized methylation (>485 000 CpG sites) and mRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8370 expression phenotypes. We identified 11 203 potential cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a false discovery rate threshold of 0.001. Most of the associations were consistent in effect size and direction of effect across sex and three ethnicities. Contrary to expectation, these eMS were not predominately enriched in promoter regions, or CpG islands, but rather in the 3' UTR, gene bodies, CpG shores or 'offshore' sites, and both positive and negative correlations between methylation and expression were observed across all locations. eMS were enriched for regions predicted to be regulatory by ENCODE (Encyclopedia of DNA Elements) data in multiple cell types, particularly enhancers. One of the strongest association signals detected (P < 2.2 × 10(-308)) was a methylation probe (cg17005068) in the promoter/enhancer region of the glutathione S-transferase theta 1 gene (GSTT1, encoding the detoxification enzyme) with GSTT1 mRNA expression. Our study provides a detailed description of the epigenetic architecture in human monocytes and its relationship to gene expression. These data may help prioritize interrogation of biologically relevant methylation loci and provide new insights into the epigenetic basis of human health and diseases.
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Jingzhong
authors.initials: J
authors.lastname: Ding
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Reynolds
authors.forename: Kurt
authors.initials: K
authors.lastname: Lohman
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Register
authors.forename: Alberto
authors.initials: A
authors.lastname: De La Fuente
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Howard
authors.forename: Greg A
authors.initials: GA
authors.lastname: Hawkins
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Jessica
authors.initials: J
authors.lastname: Morris
authors.forename: Shelly G
authors.initials: SG
authors.lastname: Smith
authors.forename: R Graham
authors.initials: RG
authors.lastname: Barr
authors.forename: Joel D
authors.initials: JD
authors.lastname: Kaufman
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Burke
authors.forename: Wendy
authors.initials: W
authors.lastname: Post
authors.forename: Steven
authors.initials: S
authors.lastname: Shea
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCall
authors.forename: David
authors.initials: D
authors.lastname: Siscovick
authors.forename: David R
authors.initials: DR
authors.lastname: Jacobs
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
authors.forename: David M
authors.initials: DM
authors.lastname: Herrington
authors.forename: Ina
authors.initials: I
authors.lastname: Hoeschele
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D009000:Monocytes / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012045:Regulatory Sequences, Nucleic Acid; D024363:Transcription Initiation Site; D059467:Transcriptome
chemical_list: C413545:glutathione S-transferase T1; D005982:Glutathione Transferase
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