Dataset Information

ANRIL Promoter DNA Methylation: A Perinatal Marker for Later Adiposity.

ABSTRACT: Experimental studies show a substantial contribution of early life environment to obesity risk through epigenetic processes. We examined inter-individual DNA methylation differences in human birth tissues associated with child's adiposity. We identified a novel association between the level of CpG methylation at birth within the promoter of the long non-coding RNA ANRIL (encoded at CDKN2A) and childhood adiposity at age 6-years. An association between ANRIL methylation and adiposity was also observed in three additional populations; in birth tissues from ethnically diverse neonates, in peripheral blood from adolescents, and in adipose tissue from adults. Additionally, CpG methylation was associated with ANRIL expression in vivo, and CpG mutagenesis in vitro inhibited ANRIL promoter activity. Furthermore, CpG methylation enhanced binding to an Estrogen Response Element within the ANRIL promoter. Our findings demonstrate that perinatal methylation at loci relevant to gene function may be a robust marker of later adiposity, providing substantial support for epigenetic processes in mediating long-term consequences of early life environment on human health.

SUBMITTER: Lillycrop K

PROVIDER: S-EPMC5440605 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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ANRIL Promoter DNA Methylation: A Perinatal Marker for Later Adiposity.

Lillycrop Karen K Murray Robert R Cheong Clara C Teh Ai Ling AL Clarke-Harris Rebecca R Barton Sheila S Costello Paula P Garratt Emma E Cook Eloise E Titcombe Philip P Shunmuganathan Bhuvaneshwari B Liew Samantha J SJ Chua Yong-Cai YC Lin Xinyi X Wu Yonghui Y Burdge Graham C GC Cooper Cyrus C Inskip Hazel M HM Karnani Neerja N Hopkins James C JC Childs Caroline E CE Chavez Carolina Paras CP Calder Philip C PC Yap Fabian F Lee Yung Seng YS Chong Yap Seng YS Melton Philip E PE Beilin Lawrie L Huang Rae-Chi RC Gluckman Peter D PD Harvey Nick N Hanson Mark A MA Holbrook Joanna D JD Godfrey Keith M KM

EBioMedicine 20170426

Experimental studies show a substantial contribution of early life environment to obesity risk through epigenetic processes. We examined inter-individual DNA methylation differences in human birth tissues associated with child's adiposity. We identified a novel association between the level of CpG methylation at birth within the promoter of the long non-coding RNA ANRIL (encoded at CDKN2A) and childhood adiposity at age 6-years. An association between ANRIL methylation and adiposity was also obs ...[more]

PMID: 28473239

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Project description:OBJECTIVE:Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans. RESEARCH DESIGN AND METHODS:Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5' from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ?5% and a 5-95% range ?10%, we related methylation status to maternal pregnancy diet and to child's adiposity at age 9 years. Replication was sought in a second independent cohort. RESULTS:In cohort 1, retinoid X receptor-? (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [?] 17% per SD change in methylation [95% CI 4-31], P = 0.009, n = 64, and ? = 20% [9-32], P < 0.001, n = 66, respectively) and %fat mass (? = 10% [1-19], P = 0.023, n = 64 and ? =12% [4-20], P = 0.002, n = 66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (? = 6% [2-10] and ? = 4% [1-7], respectively, both P = 0.002, n = 239). CONCLUSIONS:Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.

Project description:BackgroundThe early life environment may influence susceptibility to obesity and metabolic disease in later life through epigenetic processes. SLC6A4 is an important mediator of serotonin bioavailability, and has a key role in energy balance. We tested the hypothesis that methylation of the SLC6A4 gene predicts adiposity across the life course.MethodsDNA methylation at 5 CpGs within the SLC6A4 gene identified from a previous methyl binding domain array was measured by pyrosequencing. We measured DNA methylation in umbilical cord (UC) from children in the Southampton Women's Survey cohort (n = 680), in peripheral blood from adolescents in the Western Australian Pregnancy Cohort Study (n = 812), and in adipose tissue from lean and obese adults from the UK BIOCLAIMS cohort (n = 81). Real-time PCR was performed to assess whether there were corresponding alterations in gene expression in the adipose tissue.ResultsLower UC methylation of CpG5 was associated with higher total fat mass at 4 years (p = 0.031), total fat mass at 6-7 years (p = 0.0001) and % fat mass at 6-7 years (p = 0.004). Lower UC methylation of CpG5 was also associated with higher triceps skinfold thickness at birth (p = 0.013), 6 months (p = 0.038), 12 months (p = 0.062), 2 years (p = 0.0003), 3 years (p = 0.00004) and 6-7 years (p = 0.013). Higher maternal pregnancy weight gain (p = 0.046) and lower parity (p = 0.029) were both associated with lower SLC6A4 CpG5 methylation. In adolescents, lower methylation of CpG5 in peripheral blood was associated with greater concurrent measures of adiposity including BMI (p ≤ 0.001), waist circumference (p = 0.011), subcutaneous fat (p ≤ 0.001) and subscapular, abdominal and suprailiac skinfold thicknesses (p = 0.002, p = 0.008, p = 0.004, respectively). In adipose tissue, methylation of both SLC6A4 CpG5 (p = 0.019) and expression of SLC6A4 (p = 0.008) was lower in obese compared with lean adults.ConclusionsThese data suggest that altered methylation of CpG loci within SLC6A4 may provide a robust marker of adiposity across the life course.

Dataset Information

ANRIL Promoter DNA Methylation: A Perinatal Marker for Later Adiposity.

Publications

ANRIL Promoter DNA Methylation: A Perinatal Marker for Later Adiposity.

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