ANRIL Promoter DNA Methylation: A Perinatal Marker for Later Adiposity

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. •DNA methylation within the ANRIL promoter region was predictive of measures of adiposity in four independent cohorts.•DNA methylation may be a marker for late gestation fetal undernutrition, followed by rapid postnatal weight gain.•Altered DNA methylation associated with p16INK4a and p14ARF expression.•ERα may bind at the ANRIL promoter, and in vitro E2 treatment stimulated expression of ANRIL, while reducing p14 expression. The quality of the early life environment before birth can affect susceptibility to metabolic disease later in the lifecourse, with epigenetic regulation of gene function thought to be one mechanism through which early life environmental factors induce persistent phenotypic changes. In this study, using DNA from the Southampton Women's Survey (SWS), we identified changes in DNA methylation levels at birth that associated with adiposity later in childhood within the promoter of ANRIL, a gene with strong disease associations that is involved in regulatiing cellular growth. This finding was replicated in several independent cohorts, and functionally validated in adipocyte cells.