Dataset Information

DNA Methylation of Five Core Circadian Genes Jointly Contributes to Glucose Metabolism: A Gene-Set Analysis in Monozygotic Twins.

ABSTRACT: The timing of daily fluctuations in blood glucose is tightly controlled by the circadian rhythm. DNA methylation accompanies the circadian clock, and aberrant DNA methylation has been associated with circadian disruption and hyperglycemia. However, the precise role of circadian genes methylation in glucose metabolism is unknown. Using a gene-set approach in monozygotic (MZ) twin pairs, we examined the joint effect of 77 CpGs in five core circadian genes (CLOCK, BMAL1, PER1, PER2, PER3) on glucose-related traits in 138 middle-aged, male-male MZ twins (69 pairs). DNA methylation was quantified by bisulfite pyrosequencing. We first conducted matched twin pair analysis to examine the association of single CpG methylation with glucose metabolism. We then performed gene-based and gene-set analyses by the truncated product method to examine the combined effect of DNA methylation at multiple CpGs in a gene or all five circadian genes as a pathway on glucose metabolism. Of the 77 assayed CpGs, only one site was individually associated with insulin resistance at FDR < 0.05. However, the joint effect of DNA methylation in all five circadian genes together showed a significant association with glucose metabolism. Our results may unravel a biological mechanism through which circadian rhythm regulates blood glucose, and highlight the importance of testing the joint effect of multiple CpGs in epigenetic analysis.

SUBMITTER: Peng H

PROVIDER: S-EPMC6473046 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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DNA Methylation of Five Core Circadian Genes Jointly Contributes to Glucose Metabolism: A Gene-Set Analysis in Monozygotic Twins.

Peng Hao H Zhu Yun Y Goldberg Jack J Vaccarino Viola V Zhao Jinying J

Frontiers in genetics 20190412

The timing of daily fluctuations in blood glucose is tightly controlled by the circadian rhythm. DNA methylation accompanies the circadian clock, and aberrant DNA methylation has been associated with circadian disruption and hyperglycemia. However, the precise role of circadian genes methylation in glucose metabolism is unknown. Using a gene-set approach in monozygotic (MZ) twin pairs, we examined the joint effect of 77 CpGs in five core circadian genes (CLOCK, BMAL1, PER1, ...[more]

PMID: 31031806

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Project description:BackgroundRheumatoid arthritis is a common autoimmune disorder influenced by both genetic and environmental factors. Epigenome-wide association studies can identify environmentally mediated epigenetic changes such as altered DNA methylation, which may also be influenced by genetic factors. To investigate possible contributions of DNA methylation to the aetiology of rheumatoid arthritis with minimum confounding genetic heterogeneity, we investigated genome-wide DNA methylation in disease-discordant monozygotic twin pairs.MethodsGenome-wide DNA methylation was assessed in 79 monozygotic twin pairs discordant for rheumatoid arthritis using the HumanMethylation450 BeadChip array (Illumina). Discordant twins were tested for both differential DNA methylation and methylation variability between rheumatoid arthritis and healthy twins. The methylation variability signature was then compared with methylation variants from studies of other autoimmune diseases and with an independent healthy population.ResultsWe have identified a differentially variable DNA methylation signature that suggests multiple stress response pathways may be involved in the aetiology of the disease. This methylation variability signature also highlighted potential epigenetic disruption of multiple RUNX3 transcription factor binding sites as being associated with disease development. Comparison with previously performed epigenome-wide association studies of rheumatoid arthritis and type 1 diabetes identified shared pathways for autoimmune disorders, suggesting that epigenetics plays a role in autoimmunity and offering the possibility of identifying new targets for intervention.ConclusionsThrough genome-wide analysis of DNA methylation in disease-discordant monozygotic twins, we have identified a differentially variable DNA methylation signature, in the absence of differential methylation in rheumatoid arthritis. This finding supports the importance of epigenetic variability as an emerging component in autoimmune disorders.

Project description:IntroductionVan der Woude Syndrome (VWS) is an autosomal dominant disorder responsible for 2% of all syndromic orofacial clefts (OFCs) with IRF6 being the primary causal gene (70%). Cases may present with lip pits and either cleft lip, cleft lip with cleft palate, or cleft palate, with marked phenotypic discordance even among individuals carrying the same mutation. This suggests that genetic or epigenetic modifiers may play additional roles in the syndrome's etiology and variability in expression. We report the first DNA methylation profiling of 2 pairs of monozygotic twins with VWS. Our goal is to explore epigenetic contributions to VWS etiology and variable phenotypic expressivity by comparing DNAm profiles in both twin pairs. While the mutations that cause VWS in these twins are known, the additional mechanism behind their phenotypic risk and variability in expression remains unclear.MethodsWe generated whole genome DNAm data for both twin pairs. Differentially methylated positions (DMPs) were selected based on: (1) a coefficient of variation in DNAm levels in unaffected individuals < 20%, and (2) intra-twin pair absolute difference in DNAm levels >5% (delta beta > | 0.05|). We then divided the DMPs in two subgroups for each twin pair for further analysis: (1) higher methylation levels in twin A (Twin A > Twin B); and (2) higher methylation levels in twin B (Twin B >Twin A).Results and discussionGene ontology analysis revealed a list of enriched genes that showed significant differential DNAm, including clef-associated genes. Among the cleft-associated genes, TP63 was the most significant hit (p=7.82E-12). Both twin pairs presented differential DNAm levels in CpG sites in/near TP63 (Twin 1A > Twin 1B and Twin 2A < Twin 2B). The genes TP63 and IRF6 function in a biological regulatory loop to coordinate epithelial proliferation and differentiation in a process that is critical for palatal fusion. The effects of the causal mutations in IRF6 can be further impacted by epigenetic dysregulation of IRF6 itself, or genes in its pathway. Our data shows evidence that changes in DNAm is a plausible mechanism that can lead to markedly distinct phenotypes, even among individuals carrying the same mutation.

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Dataset Information

DNA Methylation of Five Core Circadian Genes Jointly Contributes to Glucose Metabolism: A Gene-Set Analysis in Monozygotic Twins.

Publications

DNA Methylation of Five Core Circadian Genes Jointly Contributes to Glucose Metabolism: A Gene-Set Analysis in Monozygotic Twins.

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