DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

Abstract

Aims/hypothesis Intrauterine growth restriction (IUGR) is associated with increased susceptibility to obesity, metabolic syndrome and type 2 diabetes. Although the mechanisms underlying the developmental origins of metabolic disease are poorly understood, evidence suggests that epigenomic alterations play a critical role. We sought to identify changes in DNA methylation patterns that are associated with IUGR in CD3 + T cells purified from umbilical cord blood obtained from male newborns who were appropriate for gestational age (AGA) or who had been exposed to IUGR. Methods CD3 + T cells were isolated from cord blood obtained from IUGR and AGA infants. The genome-wide methylation profile in eight AGA and seven IUGR samples was determined using the HELP tagging assay. Validation analysis using targeted bisulfite sequencing and bisulfite massARRAY was performed on the original cohort as well as biological replicates consisting of two AGA and four IUGR infants. The Segway algorithm was used to identify methylation changes within regulatory regions of the genome. Results A global shift towards hypermethylation in IUGR was seen compared with AGA (89.8% of 4,425 differentially methylated loci), targeted to regulatory regions of the genome, specifically promoters and enhancers. Pathway analysis identified dysregulation of pathways involved in metabolic disease (type 2 diabetes mellitus, insulin signalling, mitogen-activated protein kinase signalling) and T cell development, regulation and activation (T cell receptor signalling), as well as transcription factors (TCF3, LEF1 and NFATC) that regulate T cells. Furthermore, bump-hunting analysis revealed differentially methylated regions in PRDM16 and HLA-DPB1, genes important for adipose tissue differentiation, stem cell maintenance and function and T cell activation. Conclusions/interpretation Our findings suggest that the alterations in methylation patterns observed in IUGR CD3 + T cells may have functional consequences in targeted genes, regulatory regions and transcription factors. These may serve as biomarkers to identify those at 'high risk' for diminished attainment of full health potential who can benefit from early interventions.

Sex Differences in Nutrition, Growth, and Metabolism in Preterm Infants

“…Intrauterine growth restricted (IUGR) males and large for gestational age females had epigenetic dysregulation (48). Other reports show similar DNA hypermethylation in the promoter and enhancer regions of the genome in CD3 (+) T cells of IUGR male infants (49). These may be the biomarkers, which could potentially predict metabolic disorders when these infants grow into adulthood.…”

DNA methylation profiles in the blood of newborn term infants born to mothers with obesity

“…Differential methylation in PTPRN2 in whole blood has been associated with gestational diabetes [ 74 – 76 ], with childhood adiposity [ 76 ] as well as childhood obesity [ 77 ]. The differential methylation in PTPRN2 has also been associated with intrauterine condition such as IUGR in blood [ 78 , 79 ] but also in adults who have experienced famine, in utero [ 80 ]. These findings provide strong evidence that loci in the fetal PTPRN2 are likely modifiable with maternal nutrition, and detectable in blood later in life.…”

Long-term cardiovascular consequences of fetal growth restriction: biology, clinical implications, and opportunities for prevention of adult disease

“…134 Individuals prenatally exposed to the Dutch famine of 1944-45 had, six decades later, less DNA methylation of the imprinted insulin growth factor-2 gene compared with their unexposed, same-sex siblings. 135 Clinical studies have reported that the DNA methylation pattern in cells from cord blood 136,137 and placenta 138 between FGR human pregnancies and controls is different, affecting genes involved in metabolism and adipose tissue differentiation. Importantly, the phenotypic effects of epigenetic modifications during development may not manifest until later in life, especially if they affect pathways of genes that modulate responses to environmental challenges, such as a high-fat diet.…”