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      DNA Methylation Patterns in Cord Blood DNA and Body Size in Childhood

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          Abstract

          Background

          Epigenetic markings acquired in early life may have phenotypic consequences later in development through their role in transcriptional regulation with relevance to the developmental origins of diseases including obesity. The goal of this study was to investigate whether DNA methylation levels at birth are associated with body size later in childhood.

          Principal Findings

          A study design involving two birth cohorts was used to conduct transcription profiling followed by DNA methylation analysis in peripheral blood. Gene expression analysis was undertaken in 24 individuals whose biological samples and clinical data were collected at a mean ± standard deviation (SD) age of 12.35 (0.95) years, the upper and lower tertiles of body mass index (BMI) were compared with a mean (SD) BMI difference of 9.86 (2.37) kg/m 2. This generated a panel of differentially expressed genes for DNA methylation analysis which was then undertaken in cord blood DNA in 178 individuals with body composition data prospectively collected at a mean (SD) age of 9.83 (0.23) years. Twenty-nine differentially expressed genes (>1.2-fold and p<10 −4) were analysed to determine DNA methylation levels at 1–3 sites per gene. Five genes were unmethylated and DNA methylation in the remaining 24 genes was analysed using linear regression with bootstrapping. Methylation in 9 of the 24 (37.5%) genes studied was associated with at least one index of body composition (BMI, fat mass, lean mass, height) at age 9 years, although only one of these associations remained after correction for multiple testing ( ALPL with height, p Corrected = 0.017).

          Conclusions

          DNA methylation patterns in cord blood show some association with altered gene expression, body size and composition in childhood. The observed relationship is correlative and despite suggestion of a mechanistic epigenetic link between in utero life and later phenotype, further investigation is required to establish causality.

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          Most cited references64

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          ALSPAC--the Avon Longitudinal Study of Parents and Children. I. Study methodology.

          J. Golding, M. Pembrey, R. Jones (2001)
          ALSPAC (The Avon Longitudinal Study of Parents and Children, formerly the Avon Longitudinal Study of Pregnancy and Childhood) was specifically designed to determine ways in which the individual's genotype combines with environmental pressures to influence health and development. To date, there are comprehensive data on approximately 10,000 children and their parents, from early pregnancy until the children are aged between 8 and 9. The study aims to continue to collect detailed data on the children as they go through puberty noting, in particular, changes in anthropometry, attitudes and behaviour, fitness and other cardiovascular risk factors, bone mineralisation, allergic symptoms and mental health. The study started early during pregnancy and collected very detailed data from the mother and her partner before the child was born. This not only provided accurate data on concurrent features, especially medication, symptoms, diet and lifestyle, attitudes and behaviour, social and environmental features, but was unbiased by parental knowledge of any problems that the child might develop. From the time of the child's birth many different aspects of the child's environment have been monitored and a wide range of phenotypic data collected. By virtue of being based in one geographic area, linkage to medical and educational records is relatively simple, and hands-on assessments of children and parents using local facilities has the advantage of high quality control. The comprehensiveness of the ALSPAC approach with a total population sample unselected by disease status, and the availability of parental genotypes, provides an adequate sample for statistical analysis and for avoiding spurious results. The study has an open policy in regard to collaboration within strict confidentiality rules.
          Article 0 comments Cited 316 times – based on 0 reviews     Review now
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            Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses.

            Tim Oberlander, Joanne Weinberg, Michael Papsdorf … (2015)
            In animal models, variations in early maternal care are associated with differences in hypothalamic-pituitary-adrenal(HPA) stress response in the offspring, mediated via changes in the epigenetic regulation of glucocorticoid receptor (GR) gene (Nr3c1) expression. To study this in humans, relationships between prenatal exposure to maternal mood and the methylation status of a CpG-rich region in the promoter and exon 1F of the human GR gene (NR3C1) in newborns and HPA stress reactivity at age three months were examined. Prenatal exposure to increased third trimester maternal depressed/anxious mood was associated with increased methylation of NR3C1 at a predicted NGFI-A binding site. Increased NR3C1 methylation at this site was also associated with increased salivary cortisol stress responses at 3 months, controlling for prenatal SRI exposure, postnatal age and pre and postnatal maternal mood. The methylation status of a CpG-rich region of the NR3C1 gene, including exon 1F, in genomic DNA from cord blood mononuclear cells was quantified by bisulfite pyrosequencing in infants of depressed mothers treated with a serotonin reuptake inhibitor antidepressant (SRI) (n = 33), infants of depressed nontreated mothers (n = 13) and infants of non depressed/non treated mothers (n = 36). To study the functional implications of the newborn methylation status of NR3C1 in newborns, HPA function was assessed at three months using salivary cortisol obtained before and following a non noxious stressor and at a late afternoon basal time. Methylation status of the human NR3C1 gene in newborns is sensitive to prenatal maternal mood and may offer a potential epigenetic process that links antenatal maternal mood and altered HPA stress reactivity during infancy.
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              Adipocyte extracellular matrix composition, dynamics and role in obesity

              Edwin C. M. Mariman, Ping Wang (2010)
              The central role of the adipose tissue in lipid metabolism places specific demands on the cell structure of adipocytes. The protein composition and dynamics of the extracellular matrix (ECM) is of crucial importance for the functioning of those cells. Adipogenesis is a bi-phasic process in which the ECM develops from a fibrillar to a laminar structure as cells move from the commitment phase to the growth phase characterized by storage of vast amounts of triglycerides. Mature adipocytes appear to spend a lot of energy on the maintenance of the ECM. ECM remodeling is mediated by a balanced complement of constructive and destructive enzymes together with their enhancers and inhibitors. ECM remodeling is an energy costing process regulated by insulin, by the energy metabolism, and by mechanical forces. In the obese, overgrowth of adipocytes may lead to instability of the ECM, possibly mediated by hypoxia.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2012
                Publication date (Electronic): 14 March 2012
                Volume: 7
                Issue: 3
                Electronic Location Identifier: e31821
                Affiliations
                [1 ]HNRC, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
                [2 ]MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom
                [3 ]Musculoskeletal Research Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom
                [4 ]Bioinformatic Support Unit, Newcastle University, Newcastle upon Tyne, United Kingdom
                [5 ]Newcastle Neonatal Service, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
                [6 ]Institute of Health and Society, Newcastle University, Newcastle upon Tyne, United Kingdom
                [7 ]School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
                [8 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
                [9 ]School of Dental Sciences, University of Bristol, Bristol, United Kingdom
                [10 ]Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
                Wayne State University, United States of America
                Author notes

                Conceived and designed the experiments: CLR GDS. Analyzed the data: BStP AES CLR. Wrote the paper: CLR AG RStP AS DCS NDE MSP SMR KN JHT JT ARN SOS GDS. Undertook the follow-up of the PTBGS: NDE. Statistical support: MSP. Extracted relevant data and biological samples from the ALSPAC study: GDS SMR KN. Contributed to fat and lean mass assessment of the ALSPAC study: ARN JHT. Undertook gene expression analysis: AG. Bioinformatic support of gene expression analysis: DCS. Oversaw the Illumina GoldenGate DNA methylation analysis of ALSPAC study samples: SOS.

                Article
                Publisher ID: PONE-D-11-14003
                DOI: 10.1371/journal.pone.0031821
                PMC ID: 3303769
                PubMed ID: 22431966
                SO-VID: 2e000370-1a28-4f17-aa71-218d2e52a670
                Copyright © Relton et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 30 June 2011
                Date accepted : 16 January 2012
                Page count
                Pages: 8
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Genetics
                Subject: Epigenetics
                Subject: Gene Expression
                Subject: Molecular Cell Biology
                Subject: Gene Expression
                Subject: Medicine
                Subject: Epidemiology
                Subject: Obstetrics and Gynecology
                Subject: Pediatrics

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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