Methylomics of gene expression in human monocytes

Yongmei Liu, Jingzhong Ding, Lindsay M. Reynolds, Kurt Lohman, Thomas C. Register, Alberto De la Fuente, Timothy D. Howard, Greg A. Hawkins, Wei Cui, Jessica Morris, Shelly G. Smith, R. Graham Barr, Joel D. Kaufman, Gregory L. Burke, Wendy Post, Steven Shea, Charles E. Mccall, David Siscovick, David R. Jacobs, Russell P. TracyDavid M. Herrington, Ina Hoeschele

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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.

Original languageEnglish (US)
Article numberddt356
Pages (from-to)5065-5074
Number of pages10
JournalHuman molecular genetics
Volume22
Issue number24
DOIs
StatePublished - Dec 2013

Bibliographical note

Funding Information:
This work was supported by contracts N01-HC from the National Heart, Lung and Blood Institute and by grants (UL1-RR-024156, UL1-RR-025005) from the NIH. The MESA Epigenomics and Transcriptomics Study was funded by a National Heart, Lung and Blood Institute grant (R01HL101250) to Wake Forest University Health Sciences. The Encyclopedia of DNA Elements (ENCODE) project data generation and analysis was supported by funds from the National Human Genome Research Institute (ENCODE), the Burroughs Wellcome Fund, Howard Hughes Medical Institute, National Science Foundation, Sloan Foundation, Massachusetts General Hospital and the Broad Institute. ENCODE data comes from grants led by Bradley Bernstein (Broad Institute), Richard Myers (HudsonAlpha Institute), Michael Snyder (Stanford), Gregory Crawford (Duke) and John Stamatoyannopoulos (University of Washington).

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