Dynamic Changes in DNA Methylation Occur during the First Year of Life in Preterm Infants

Abstract

BackgroundPreterm birth associates with a substantially increased risk of later cardiovascular disease and neurodevelopmental disorders. Understanding underlying mechanisms will facilitate the development of screening and intervention strategies to reduce disease risk. Changes in DNA methylation have been proposed as one mechanism linking the early environment with later disease risk. We tested the hypothesis that preterm birth associates with altered DNA methylation in genes encoding insulin-like growth factor 2 (IGF2) and FK506-binding protein 5 (FKBP5), which appear particularly vulnerable to early life adversity.MethodsFifty preterm infants were seen and assessed at birth, term equivalent age, 3 months and 1-year corrected ages; 40 term infants were seen at birth, 3 months and 1 year. Saliva was collected for DNA extraction at birth, term, and 1 year. Pyrosequencing of bisulfite-converted DNA was performed to measure DNA methylation at specific CpG sites within the IGF2 and FKBP5 loci.ResultsWeight and head circumference was reduced in preterm infants at all time points. Preterm infants had a higher percentage body fat at term-corrected age, but this difference was not persistent. DNA methylation at the differentially methylated region (DMR) of IGF2 (IGF2DMR2) and FKBP5 was lower in preterm infants at birth- and term-corrected age compared to term infants at birth. IGF2DMR2 and FKBP5 methylation was related to birthweight SD score in preterm infants. Among preterm infants, social deprivation was an independent contributor toward reducing DNA methylation at IGF2DMR2 at birth- and term-corrected age and maternal smoking was associated with reduced DNA methylation at FKBP5 at birth. There were no persistent differences in DNA methylation at 1 year of age.ConclusionChanges in DNA methylation were identified at key regions of IGF2/H19 and FKBP5 in preterm infants in early life. Potential contributing factors include maternal smoking and social deprivation. However, these changes did not persist at 1 year of age and further longitudinal studies are required to determine any associations between altered DNA methylation in the perinatal period of individuals born preterm and their long-term health.

Hsp90 and FKBP51: complex regulators of psychiatric diseases

“…Similar alterations in FKBP5 DNA methylation have also been associated with preterm birth. FKBP5 DNA methylation was lower in preterm infants compared to term equivalent-age infants [93]. This decreased methylation was restored to normal levels by 1 year of age.…”

Methylation of the FKBP5 gene in association with FKBP5 genotypes, childhood maltreatment and depression

“…According to Klengel et al [5], the enhanced risk of stressrelated disorders in T allele carriers is mediated by reduced DNA methylation in glucocorticoid response elements of the FKBP5 gene after CM exposure. DNA methylation is an essential part of gene regulation and associated with homoeostatic functioning like genomic imprinting, silencing of repetitive DNA elements and proper expression of genetic information [17][18][19][20][21]. Interactive effects between the rs1360780 genotype and stressful life events were reported to reduce the methylation levels [5,9,10,21].…”

Alterations in glucose concentrations affect DNA methylation at Lrg1 in an ex vivo rat cortical slice model of preterm brain injury

“…Samples were analysed from a cohort of infants recruited within the first week of life from the Simpson Centre for Reproductive Health, Edinburgh, UK, with informed written parental consent. Details of sample collection and the demographic details of these infants and their mothers have been reported elsewhere (Piyasena et al ., ). From an original cohort of 50 preterm (< 32 weeks gestation) and 40 term infants (37–42 weeks gestation) recruited at birth and followed up for 1 year, buccal cell DNA was available from 32 preterm infants at term corrected age and 30 term infants at birth, and from 37 preterm infants at 1 year corrected age and 34 of the term infants at 1 year.…”