The MESA Epigenomics and Transcriptomics Study was funded by a National Heart, Lung and Blood Institute grant (R01HL101250) through the NIH Roadmap Epigenomics Program in 2009. Leveraging MESA exam 5 (2010-2012), we purified fresh monocytes and CD4+ T cells from 2,600 MESA participants (Caucasian, African American, and Hispanic men and women aged 55 - 94 years) across the four MESA field centers (Forsyth County, NC; Baltimore, MD; New York, NY; and St. Paul, MN).
Our ongoing global gene expression and DNA methylation studies uses the Illumina microarray, RNAseq, and miRNAseq technologies. The rich MESA database will enable the epigenomic and transcriptomic study of the genetic, physiological, environmental and clinical characteristics of the MESA population.
expression-associated Methylation Site (eMS) Database
A project has been launched to investigate potential gene expression regulatory methylation sites in humans by examining the association between CpG methylation and gene expression in purified human monocytes from a large study population (1,264 community-dwelling participants in the Multi-Ethnic Study of Atherosclerosis (MESA)). The Illumina HumanHT-12 v4 Expression BeadChip and the Illumina HumanMethylation450 BeadChip were used to provide genome-wide coverage of mRNA expression and DNA methylation, respectively. This data enabled us to identify 11,203 potential cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a False Discovery Rate (FDR) threshold of 0.001.
eMS Database Details
The eMS Database is used to store the methylation-gene expression association results from 11,203 CpG sites with expression-associated methylation, and to enable a convenient search for genes and eMS. Particularly, we focus on cis-acting genetic regulation, defined as associations between CpG methylation sites within 1 MB of expressed transcripts (from the transcription start site). Each of these associations were performed using a linear regression model adjusted for age, sex, ethnicity, study site, expression/methylation chip, methylation position (for age-CpG methylation analyses only), and residual sample contamination with non-targeted cells (see publication for methods). The primary outcome was gene expression levels, and the main predictor was CpG methylation levels.
Citing MESA EpiGenomics Resources
When using data from the eMS Database in a research work that will be published in a journal or on the internet, please cite the following publication: 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 Jr; Russell P. Tracy; David M. Herrington; Ina Hoeschele; Hum Mol Genet 22 (24), 5065-5074 (2013)
Query the MESA EpiGenomics eMS Database:
- expression-associated Methylation Site (eMS) Database
Download the MESA EpiGenomics eMS Database (xls):
Methylomics of Gene Expression in Human Monocytes
Liu Y, Ding J, Reynolds LM, Lohman K, Register TC, De La Fuente A, Howard TD, Hawkins GA, Cui W, Morris J, Smith SG, Barr RG, Kaufman JD, Burke GL, Post W, Shea S, McCall CE, Siscovick D, Jacobs DR Jr, Tracy RP, Herrington DM, Hoeschele I.
Hum Mol Genet. 2013 Dec 15;22(24):5065-74. doi: 10.1093/hmg/ddt356. Epub 2013 Jul 29.
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=1,264), we characterized methylation (>485,000 CpG sites) and mRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8,370 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 (FDR) 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 data in multiple cell types, particularly enhancers. One of the strongest association signals detected (p<2.2x10-308) 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.
Reynolds LM1, Taylor JR2, Ding J3, Lohman K4, Johnson C5, Siscovick D6, Burke G7, Post W8, Shea S9, Jacobs DR Jr10, Stunnenberg H11, Kritchevsky SB3, Hoeschele I12, McCall CE13, Herrington DM14, Tracy RP15, Liu Y16.
Nat Commun. 2014 Nov 18;5:5366. doi: 10.1038/ncomms6366.
Age-related variations in DNA methylation have been reported; however, the functional relevance of these differentially methylated sites (age-dMS) are unclear. Here we report potentially functional age-dMS, defined as age- and cis-gene expression-associated methylation sites (age-eMS), identified by integrating genome-wide CpG methylation and gene expression profiles collected ex vivo from circulating T cells (227 CD4+ samples) and monocytes (1,264 CD14+ samples, age range: 55-94 years). None of the age-eMS detected in 227 T-cell samples are detectable in 1,264 monocyte samples, in contrast to the majority of age-dMS detected in T cells that replicated in monocytes. Age-eMS tend to be hypomethylated with older age, located in predicted enhancers and preferentially linked to expression of antigen processing and presentation genes. These results identify and characterize potentially functional age-related methylation in human T cells and monocytes, and provide novel insights into the role age-dMS may have in the aging process.
Reynolds LM1, Ding J2, Taylor JR3, Lohman K4, Soranzo N5, de la Fuente A6, Liu TF7, Johnson C8, Barr RG9, Register TC10, Donohue KM11, Talor MV12, Cihakova D13, Gu C14, Divers J15, Siscovick D16, Burke G17, Post W18, Shea S19, Jacobs DR Jr20, Hoeschele I21, McCall CE22,23, Kritchevsky SB24,25, Herrington D26, Tracy RP27, Liu Y28.
BMC Genomics. 2015 Apr 22;16:333. doi: 10.1186/s12864-015-1522-4.
BACKGROUND: Transcriptomic studies hold great potential towards understanding the human aging process. Previous transcriptomic studies have identified many genes with age-associated expression levels; however, small samples sizes and mixed cell types often make these results difficult to interpret.RESULTS: Using transcriptomic profiles in CD14+ monocytes from 1,264 participants of the Multi-Ethnic Study of Atherosclerosis (aged 55-94 years), we identified 2,704 genes differentially expressed with chronological age (false discovery rate, FDR ≤ 0.001). We further identified six networks of co-expressed genes that included prominent genes from three pathways: protein synthesis (particularly mitochondrial ribosomal genes), oxidative phosphorylation, and autophagy, with expression patterns suggesting these pathways decline with age. Expression of several chromatin remodeler and transcriptional modifier genes strongly correlated with expression of oxidative phosphorylation and ribosomal protein synthesis genes. 17% of genes with age-associated expression harbored CpG sites whose degree of methylation significantly mediated the relationship between age and gene expression (p < 0.05). Lastly, 15 genes with age-associated expression were also associated (FDR ≤ 0.01) with pulse pressure independent of chronological age. Comparing transcriptomic profiles of CD14+ monocytes to CD4+ T cells from a subset (n = 423) of the population, we identified 30 age-associated (FDR < 0.01) genes in common, while larger sets of differentially expressed genes were unique to either T cells (188 genes) or monocytes (383 genes). At the pathway level, a decline in ribosomal protein synthesis machinery gene expression with age was detectable in both cell types.CONCLUSIONS: An overall decline in expression of ribosomal protein synthesis genes with age was detected in CD14+ monocytes and CD4+ T cells, demonstrating that some patterns of aging are likely shared between different cell types. Our findings also support cell-specific effects of age on gene expression, illustrating the importance of using purified cell samples for future transcriptomic studies. Longitudinal work is required to establish the relationship between identified age-associated genes/pathways and aging-related diseases.
Ding J1, Reynolds LM2, Zeller T3, Müller C3, Lohman K2, Nicklas BJ1, Kritchevsky SB1, Huang Z4, de la Fuente A5, Soranzo N6, Settlage RE7, Chuang CC8, Howard T1, Xu N9, Goodarzi MO9, Chen YD10, Rotter JI10, Siscovick DS11, Parks JS8, Murphy S4, Jacobs DR Jr12, Post W13, Tracy RP14, Wild PS15, Blankenberg S3, Hoeschele I7, Herrington D1, McCall CE1, Liu Y16.
Diabetes. 2015 Oct;64(10):3464-74. doi: 10.2337/db14-1314. Epub 2015 Jul 7.
Obesity is linked to type 2 diabetes (T2D) and cardiovascular diseases; however, the underlying molecular mechanisms remain unclear. We aimed to identify obesity-associated molecular features that may contribute to obesity-related diseases. Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis (MESA) participants, we quantified the transcriptome and epigenome. We discovered that alterations in a network of coexpressed cholesterol metabolism genes are a signature feature of obesity and inflammatory stress. This network included 11 BMI-associated genes related to sterol uptake (↑LDLR, ↓MYLIP), synthesis (↑SCD, FADS1, HMGCS1, FDFT1, SQLE, CYP51A1, SC4MOL), and efflux (↓ABCA1, ABCG1), producing a molecular profile expected to increase intracellular cholesterol. Importantly, these alterations were associated with T2D and coronary artery calcium (CAC), independent from cardiometabolic factors, including serum lipid profiles. This network mediated the associations between obesity and T2D/CAC. Several genes in the network harbored C-phosphorus-G dinucleotides (e.g., ABCG1/cg06500161), which overlapped Encyclopedia of DNA Elements (ENCODE)-annotated regulatory regions and had methylation profiles that mediated the associations between BMI/inflammation and expression of their cognate genes. Taken together with several lines of previous experimental evidence, these data suggest that alterations of the cholesterol metabolism gene network represent a molecular link between obesity/inflammation and T2D/CAC.
Reynolds LM, Wan M, Ding J, Taylor JR, Lohman K, Su D, Bennett BD, Porter DK, Gimple R, Pittman GS, Wang X, Howard TD, Siscovick D, Psaty BM, Shea S, Burke GL, Jacobs DR Jr, Rich SS, Hixson JE, Stein JH, Stunnenberg H, Barr RG, Kaufman JD, Post WS, Hoeschele I, Herrington DM, Bell DA, Liu Y.
Circ Cardiovasc Genet. 2015 Oct;8(5):707-16. doi: 10.1161/CIRCGENETICS.115.001097. Epub 2015 Aug 25.
BACKGROUND: Tobacco smoke contains numerous agonists of the aryl hydrocarbon receptor (AhR) pathway, and activation of the AhR pathway was shown to promote atherosclerosis in mice. Intriguingly, cigarette smoking is most strongly and robustly associated with DNA modifications to an AhR pathway gene, the AhR repressor (AHRR). We hypothesized that altered AHRR methylation in monocytes, a cell type sensitive to cigarette smoking and involved in atherogenesis, may be a part of the biological link between cigarette smoking and atherosclerosis.METHODS AND RESULTS: DNA methylation profiles of AHRR in monocytes (542 CpG sites±150 kb of AHRR, using Illumina 450K array) were integrated with smoking habits and ultrasound-measured carotid plaque scores from 1256 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Methylation of cg05575921 significantly associated (P=6.1×10(-134)) with smoking status (current versus never). Novel associations between cg05575921 methylation and carotid plaque scores (P=3.1×10(-10)) were identified, which remained significant in current and former smokers even after adjusting for self-reported smoking habits, urinary cotinine, and well-known cardiovascular disease risk factors. This association replicated in an independent cohort using hepatic DNA (n=141). Functionally, cg05575921 was located in a predicted gene expression regulatory element (enhancer) and had methylation correlated with AHRR mRNA profiles (P=1.4×10(-17)) obtained from RNA sequencing conducted on a subset (n=373) of the samples.CONCLUSIONS: These findings suggest that AHRR methylation may be functionally related to AHRR expression in monocytes and represents a potential biomark