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Widespread Discordance of DNA Methylation Between two Accessible Human Tissues

ABSTRACT: Inter-individual variability in DNA methylation has been hypothesized to contribute to complex phenotypes through epigenetic modulation of gene expression levels. Population epigenetic studies have been examining differences in DNA methylation in a variety of accessible tissues for association with specific diseases or exposures, but relatively little is known about how this inter-individual variation differs between tissues. This study presents an analysis of global DNA methylation differences between matched peripheral blood mononuclear cells and buccal epithelial cells; specifically it examines differential DNA methylation, probe-wise DNA methylation variance, and how methylation relates to a number of demographic factors across the two tissues. We found that peripheral blood mononuclear cells have overall higher DNA methylation than buccal epithelial cells, and regions of the genome that are differently methylated between the tissues tend to have low CpG density. We also discovered that although both tissues show extensive probe-wise variability, the specific regions and magnitude of variability differed between tissues. Finally, we observed that while both buccal epithelial and peripheral mononuclear blood cell DNA methylation was associated with gender, only methylation of the latter was associated with body mass index. The work presented here offers insight into variability of DNA methylation between individuals and across tissues and the suitability of buccal epithelial and peripheral mononuclear cells for the biological questions explored by epigenome-wide association studies in human populations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE53396 | GEO | 2014/05/31

SECONDARY ACCESSION(S): PRJNA231916

REPOSITORIES: GEO

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Project description:Neuroepigenetics considers genetic sequences and the interplay with environmental influences to elucidate vulnerability risk for various neurological and psychiatric disorders. However, evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues were used, resulting in limited progress compared with other epigenetic studies, such as cancer research. Therefore, we developed databases to establish correlations between the brain and peripheral tissues in the same individuals. Four tissues, resected brain tissue, blood, saliva, and buccal mucosa (buccal), were collected from 19 patients (aged 13–73 years) who underwent neurosurgery. Moreover, their genome-wide DNA methylation was assessed using the Infinium HumanMethylationEPIC BeadChip arrays to determine the cross-tissue correlation of each combination. These correlation analyses were conducted with all methylation sites and with variable CpGs, and with when these were adjusted for cellular proportions. For the averaged data for each CpG across individuals, the saliva–brain correlation (r = 0.90) was higher than that for blood–brain (r = 0.87) and buccal–brain (r = 0.88) comparisons. Among individual CpGs, blood had the highest proportion of CpGs correlated to the brain at nominally significant levels (19.0%), followed by saliva (14.4%) and buccal (9.8%). These results were similar to the previous IMAGE-CpG results; however, the correlation analysis between the correlation coefficients of the datasets revealed a relatively low degree of correlation (brain vs. blood: r = 0.27, saliva; r = 0.18, and buccal; r = 0.24). To the best of our knowledge, this is the fourth study in the literature initiating the development of databases for correlations between the brain and peripheral tissues in the same individuals. We present the first database developed from an Asian population, specifically Japanese samples (AMAZE-CpG), which would contribute to interpreting individual epigenetic study results from various Asian populations.

Project description:Background DNA methylation has been recognized as a key mechanism in cell differentiation. Various studies have compared tissues to characterize epigenetically regulated genomic regions, but due to differences in study design and focus there still is no consensus as to the annotation of genomic regions predominantly involved in tissue-specific methylation. We used a new algorithm to identify and annotate tissue-specific Differentially Methylated Regions (tDMRs) in Illumina 450k chip data on four peripheral (blood, saliva, buccal swab and hair follicles) and six internal tissues (liver, muscle, pancreas, subcutaneous fat, omentum, spleen with matched blood samples). Results The majority of tDMRs, in both relative and absolute terms, occurred in CpG-poor regions. Further analysis revealed that these regions were associated with alternative transcription events (alternative first exons, mutually exclusive exons and cassette exons). Only a minority of tDMRs mapped to gene-body CpG islands (13%) or CpG islands shores (25%) suggesting a less prominent role for these regions than indicated previously. Implementation of ENCODE annotations showed enrichment of tDMRs in DNase hypersensitive sites and transcription factor binding sites. Despite the predominance of tissue differences, inter-individual differences in DNA methylation in internal tissues were correlated with that in blood for a subset of CpG sites in a locus and tissue-specific manner. Conclusions We conclude that tDMRs preferentially occur in CpG-poor regions and are associated with alternative transcription. Furthermore, our data suggest the utility of creating an atlas cataloguing variably methylated regions in internal tissues that are marked by DNA methylation measured in easy accessible peripheral tissues. Comparison of four peripheral (blood, saliva, buccal swab and hair follicles in n=5) and six internal tissues (liver, muscle, pancreas, subcutaneous fat, omentum, spleen with matched blood samples in n=6).

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Widespread Discordance of DNA Methylation Between two Accessible Human Tissues

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