Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptomics and methylomics of human monocytes [methylome]

ABSTRACT: The MESA Epigenomics and Transcriptomics Study 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 (community-dwelling participants in the Multi-Ethnic Study of Atherosclerosis (MESA)). 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. The current study is particularly focused on the relationships between transcriptomics and methylomics with age. Data includes transcriptomic and methylomic data from CD14+ samples, collected from 1,202 individuals ranging 44 - 83 years of age (Exam 1). Peripheral monocytes were isolated from blood (Exam 5) with anti-CD14 coated magnetic beads, and 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 CpG loci whose degree of methylation was associated with age (age-DMR),and identify age- and expression-associated methylation sites (age-eMS), whose degree of methylation was associated with age and cis-gene expression (+/- 1Mb), after adjusting for other covariates such as race, gender, study site, and sample contaimination with B-cells, T-cells, natural killer cells, and neutrophils. To estimate residual sample contamination for monocyte data analysis, separate enrichment scores for neutrophils, B cells, T cells, and natural killer cells were calculated and provided as sample characteristics. The participant race, gender, and study site were provided as 'raceGenderSite variable' which represents a combination of those factors. A detailed description of each sample characteristics is included in the 'README.txt'.

ORGANISM(S): Homo sapiens

SUBMITTER: Yongmei Liu

PROVIDER: E-GEOD-56046 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Age-related variations in the methylome associated with gene expression in human monocytes and T cells.

Reynolds Lindsay M LM Taylor Jackson R JR Ding Jingzhong J Lohman Kurt K Johnson Craig C Siscovick David D Burke Gregory G Post Wendy W Shea Steven S Jacobs David R DR Stunnenberg Hendrik H Kritchevsky Stephen B SB Hoeschele Ina I McCall Charles E CE Herrington David D Tracy Russell P RP Liu Yongmei Y

Nature communications 20141118

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 ...[more]

PMID: 25404168

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Project description:Epigenetic control of gene transcription is critical for normal human development and cellular differentiation. While alterations of epigenetic marks such as DNA methylation have been linked to cancers and many other human diseases, interindividual epigenetic variation in normal tissues due to aging, environmental factors, or innate susceptibility are poorly characterized. The plasticity, tissue-specific nature, and variability of gene expression are related to epigenomic states that vary across individuals. Thus, population-based investigations are needed to further our understanding of the fundamental dynamics of normal individual epigenomes. We analyzed 217 non-pathologic human tissues from 10 anatomic sites at 1413 autosomal CpG loci associated with 773 genes to investigate tissue-specific differences in DNA methylation, and to discern how aging and exposures contribute to normal variation in methylation. Methylation profile classes derived from unsupervised modeling were significantly associated with age (P < 0.0001), and were significant predictors of tissue origin (P < 0.0001). In solid tissues (n=119) we found striking, highly significant CpG island dependent correlations between age and methylation; loci in CpG islands gained methylation with age, loci not in CpG islands lost methylation with age (P < 0.001), and this pattern was consistent across tissues and in an analysis of blood-derived DNA. Our data clearly demonstrate age and exposure related differences in tissue-specific methylation, and significant age associated methylation patterns which are CpG island context dependent. This work provides novel insight into the role of aging and the environment in susceptibility to diseases such as cancer, and critically informs the field of epigenomics by providing evidence of epigenetic dysregulation by age-related methylation alterations. Collectively we reveal key issues to consider both in the construction of reference. The causes and extent of tissue-specific interindividual variation in human epigenomes are underappreciated and hence, poorly characterized. We surveyed over 200 carefully annotated human tissue samples from ten anatomic sites at 1413 CpGs for methylation alterations to appraise the nature of phenotypically, and hence potentially clinically important epigenomic alterations. Within tissue types, across individuals, we found variation in methylation that was significantly related to aging and environmental exposures such as tobacco smoking. Individual variation in age and exposure-related methylation may significantly contribute to increased susceptibility to several diseases. As the NIH-funded HapMap project is critically contributing to annotating the human reference genome defining normal genetic variability, our work raises key issues to consider in the construction of reference epigenomes. It is well recognized that understanding genetic variation is essential to understanding disease. Our work, and the known interplay of epigenetics and genetics, makes it equally clear that a more complete characterization of epigenetic variation and its sources must be accomplished to reach the goal of a complete understanding of disease. Additional research is absolutely necessary to define the mechanisms controlling epigenomic variation. We have begun to lay the foundations for essential normal tissue controls for comparison to diseased tissue, which will allow the identification of the most crucial disease-related alterations and provide more robust targets for novel treatments. Normal human tissues were assembled by a collaborative, multi-institutional network of investigators conducting molecular epidemiologic studies of human cancer. Tissues were obtained through Institutional Review Board approved studies already underway at these institutions, or were obtained from the National Disease Research Interchange (NDRI, Philadelphia, PA). Briefly, normal brain tissues (n=12) were contributed by the Wiencke lab at UCSF through the San Francisco Adult Glioma Study (Wiemels JL, Int J Ca 2002). Normal lung tissues (n=49) were obtained from adjacent non-tumor portions of lung in patients treated for NSCLC (Wiencke JK, Ca Res, 1995) or from the NDRI from non-diseased individuals at autopsy (n=4). Peripheral blood DNA was obtained from controls enrolled in a study of bladder cancer (n=15) (Karagas MR, Env Health Persp 1998), controls enrolled in a study of head and neck cancer (n=15) (Peters ES, CEBP 2005, 14:476-82), and newborn infants (n=55) (Urayama KY, CEBP, 2007, 16:1172). Non-tumorigenic pleural samples (n=18) were obtained from grossly disease-uninvolved regions of incident mesothelioma (Christensen BC, Carcinogenesis 2008). Head and neck anatomic sites (n=11), bladder (n=5), kidney (n=6), and small intestine (n=5) were obtained from the NDRI, all from individuals with no gross diseases or tumors of the obtained tissues. Non-pathologic placenta samples (n=19) were obtained as residual tissues from control infant term births as part of an ongoing hospital-based case-control study of intrauterine growth restriction at Women and Infants Hospital in Providence RI. All tissues obtained from patients with disease (lung, pleura) were histologically confirmed as normal by independent study pathologist review of tissue samples prior to DNA extraction.

Dataset Information

Transcriptomics and methylomics of human monocytes [methylome]

Publications

Age-related variations in the methylome associated with gene expression in human monocytes and T cells.

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