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Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly.

ABSTRACT: The AXIN1 gene has been implicated in caudal duplication anomalies. Its coding region was sequenced in both members of a monozygotic (MZ) twin pair discordant for a caudal duplication anomaly, but no mutation was found. Using bisulfite sequencing, we examined methylation at the promoter region of the AXIN1 gene in these twins and in twin and age-matched singleton controls. Methylation of the promoter region in peripheral blood mononucleated cells was variable among individuals, including MZ pairs. In the MZ pair discordant for the caudal duplication, this region of the affected twin was significantly more methylated than that of the unaffected twin (P < .0001), which was significantly more methylated than those of the controls (P = .02). We have confirmed that this CpG island does function as a promoter in vitro and that its activity is inversely proportional to the extent of methylation. This finding raises the possibility that hypermethylation of the AXIN1 promoter, by mechanisms as yet undetermined, is associated with the malformation. This case may be paradigmatic for some cases of MZ discordance.

SUBMITTER: Oates NA

PROVIDER: S-EPMC1474116 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly.

Oates N A NA van Vliet J J Duffy D L DL Kroes H Y HY Martin N G NG Boomsma D I DI Campbell M M Coulthard M G MG Whitelaw E E Chong S S

American journal of human genetics 20060522 1

The AXIN1 gene has been implicated in caudal duplication anomalies. Its coding region was sequenced in both members of a monozygotic (MZ) twin pair discordant for a caudal duplication anomaly, but no mutation was found. Using bisulfite sequencing, we examined methylation at the promoter region of the AXIN1 gene in these twins and in twin and age-matched singleton controls. Methylation of the promoter region in peripheral blood mononucleated cells was variable among individuals, including MZ pair ...[more]

PMID: 16773576

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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:BackgroundPrenatal growth restriction and low birth weight have been linked to long-term alterations of health, presumably via adaptive modifications of the epigenome. Recent studies indicate a plasticity of the 11p15 epigenotype in response to environmental changes during early stages of human development.Study designWe analyzed methylation levels at different 11p15 loci in 20 growth-discordant monozygotic twin pairs. Intrauterine development was discordant due to severe twin-to-twin transfusion syndrome (TTTS), which was treated by fetoscopic laser coagulation of communicating vessels before 25 weeks of gestation. Methylation levels at age 4 were determined in blood and buccal cell-derived DNA by the single nucleotide primer extension reaction ion pair reverse-phase high performance liquid chromatography (SNuPE IP RP HPLC) assay. Methylation at LINE-1 repeats was analyzed as an estimate of global methylation.ResultsIn general, variance of locus-specific methylation levels appeared to be higher in buccal cell- as compared to blood cell-derived DNA samples. Paired analyses within the twin pairs revealed significant differences at only one CpG site (IGF2 dmr0 SN3 (blood), +1.9% in donors; P = 0.013). When plotting the twin pair-discordance in birth weight against the degree of discordance in site-specific methylation at age 4, only a few CpGs were found to interact (one CpG site each at IGF2dmr0 in blood/saliva DNA, one CpG at LINE-1 repeats in saliva DNA), with 26 to 36% of the intra-twin pair divergence at these sites explained by prenatal growth discordance. However, across the entire cohort of 40 children, site-specific methylation did not correlate with SD-scores for weight or length at birth. Insulin-like growth factor-II serum concentrations showed significant within-twin pair correlations at birth (R = 0.57) and at age 4 (R = 0.79), but did not differ between donors and recipients. They also did not correlate with the analyzed 11p15 methylation parameters.ConclusionIn a cohort of 20 growth-discordant monozygotic twin pairs, severe alteration in placental blood supply due to TTTS appears to leave only weak, if any, epigenetic marks at the analyzed CpG sites at 11p15.

Project description:PurposeMonozygotic (MZ) twin pairs discordant for disease allow careful examination of environmental factors whilst controlling for genetic variation. The purpose of this study was to examine differences in environmental risk factors in MZ twins discordant for myopia.MethodsSixty four MZ twin pairs discordant for refractive error were interviewed. Discordant twins were selected from 1326 MZ twin pairs from the TwinsUK adult twin registry with non-cycloplegic autorefraction. Discordancy was defined as ≥ 2 Dioptres (D) difference in spherical equivalent (SphE) and discordant for class of refractive error. In a 35-item telephone questionnaire twins were separately asked (and scored) about the risk factors urban/rural residence, occupational status and highest educational level. They responded with more (1), less (-1) or the same (0) as their twin on time spent outside, playing outdoor sport, and on close work aged <16 and 16-25 years. The lower SphE twin's score was subtracted from the higher SphE twin's score, and mean values of the difference calculated for each variable.ResultsSixty four twin pairs were included (mean age 56, range 30-79 years; mean difference in refraction 3.35 D, S.D. 1.55 D, median difference 2.78 D). Within discordant MZ twin pairs, the more myopic twin was associated with having a higher occupational status (mean score between 16 and 25 years -0.11; 95% CI -0.19 to -0.04; mean score aged >25 years -0.23, 95% CI -0.28 to -0.17), being resident in urban area (mean score -0.26; 95% CI -0.33 to -0.18) and performing more close work (mean score <16 years -0.11; 95% CI -0.18 to -0.05; mean score aged 16-25 years -0.17, 95% CI -0.24 to -0.10) than their twin. The twins who spent more time outdoors (mean score <16 years 0.09; 95% CI 0.03-0.15; mean score aged 16-25 years 0.28, 95% CI 0.15-0.41) or performed more outdoors sports (mean score <16 years 0.13; 95% CI 0.04-0.21; mean score aged 16-25 years 0.23, 95% CI 0.10-0.36) were less likely to be myopic than their twin.ConclusionsThis study has confirmed known environmental risk factors for myopia. These data will allow selection of discordant twins for epigenetic analysis to advance knowledge of mechanisms of refractive error development.

Dataset Information

Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly.

Publications

Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly.

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