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Placental and Cord Blood Methylation of Genes Involved in Energy Homeostasis: Association with Fetal Growth and Neonatal Body Composition

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Placental and Cord Blood Methylation of Genes Involved in Energy Homeostasis: Association with Fetal Growth and Neonatal Body Composition Diabetes Volume 66, March 2017 779 Marta Díaz,1,2 Cristina García,1,2 Giorgia Sebastiani,1,2 Francis de Zegher,3 Abel López-Bermejo,4,5 and Lourdes Ibáñez1,2 Placental and Cord Blood Methylation of Genes Involved in Energy Homeostasis: Association With Fetal Growth and Neonatal Body Composition Diabetes 2017;66:779–784 | DOI: 10.2337/db16-0776 GENETICS/GENOMES/PROTEOMICS/METABOLOMICS Low weight at birth is associated with subsequent suscep- metabolic syndrome, and, subsequently, cardiovascular tibility to diabetes. Epigenetic modulation is among disease and type 2 diabetes in adulthood (1,2). Growth the mechanisms potentially mediating this association. restraint before birth is thought to confer such risk, par- We performed a genome-wide DNA methylation anal- ticularly when followed by excessive weight gain after birth ysis in placentas from term infants born appropriate- (3). By the postnatal age of 4 months, SGA infants already for-gestational-age (AGA) or small-for-gestational-age have an altered endocrine-metabolic profile with elevated (SGA) to identify new genes related to fetal growth and concentrations of circulating IGF-I and high–molecular neonatal body composition. Candidate genes were vali- weight adiponectin (4). These abnormalities are influenced by fi dated by bisul te pyrosequencing (30 AGA, 21 SGA) and early nutrition and evolve toward a profile that includes more also analyzed in cord blood. Gene expression analyses hepatic and visceral adiposity in childhood (5). The mecha- were performed by RT-PCR. Neonatal body composition nisms underpinning these abnormalities remain poorly was assessed by dual X-ray absorptiometry at age 2 weeks. understood. The ATG2B, NKX6.1, and SLC13A5 genes (respectively re- latedtoautophagy,b-cell development and function, and Epigenetic regulation of the placenta evolves during lipid metabolism) were hypermethylated in placenta and cord preimplantation and progresses further during gestation. blood from SGA newborns, whereas GPR120 (related to Strictly regulated DNA methylation has a key role in tissue- fi free fatty acid regulation) was hypomethylated in placenta speci c gene regulation and transcription; DNA methyl- and hypermethylated in cord blood. Gene expression levels ation in CpG islands has been the most investigated target were opposite to methylation status, and both correlated so far (6). Although DNA methylation has traditionally with birth weight, circulating IGF-I, and total and abdominal been viewed as an epigenetic “silencing” mark, recent ad- fat at age 2 weeks. In conclusion, alterations in methylation vances suggest that the impact of DNA methylation on and expression of genes involved in the regulation of energy gene expression depends more on the genomic location homeostasis were found to relate to fetal growth and neo- of the CpG site (7). An adverse intrauterine environment natal body composition and thus may be among the early can modify placental epigenetic marks and gene expression mechanisms modulating later susceptibility to diabetes. profiles, resulting in fetal growth restraint (8–10). Differ- ential patterns of placental and cord blood methylation and/or expression have been described in selected imprinted Individuals born small-for-gestational-age (SGA) are at and nonimprinted genes (11,12) in heterogeneous popula- increased risk for developing insulin resistance, obesity, tions, including preterm infants (11) and growth-restricted 1Institut Pediàtric, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain This article contains Supplementary Data online at http://diabetes 2CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain .diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0776/-/DC1. 3 Department of Development and Regeneration, University of Leuven, Leuven, Belgium © 2017 by the American Diabetes Association. Readers may use this article as 4 Department of Pediatrics, Dr. Josep Trueta Hospital, Girona, Spain long as the work is properly cited, the use is educational and not for profit, and the 5 Girona Institute for Biomedical Research, Girona, Spain work is not altered. More information is available at http://www.diabetesjournals Corresponding author: Lourdes Ibáñez, [email protected]. .org/content/license. Received 25 June 2016 and accepted 9 December 2016. 780 Gene Methylation/Expression in SGA Placenta/Cord Diabetes Volume 66, March 2017 fetuses from pregnancies complicated by hypertension or GAT-39; NKX6.1:forward59-CTTCTGGCCCGGAGTGAT-39, preeclampsia (12). Genome-wide methylation abnormalities reverse 59-CCCGCCAAGTATTTTGTTTG-39; SLC13A5: for- in adipose-derived stem cells from SGA individuals have also ward 59- CCTGCTGGATTGGAAGGTAA-39, reverse 59-CAC been reported (13). TCAGTGAACACGGCAAC-39; GAPDH: forward 59-GTCAG We tested whether placental and cord blood methyl- TGGTGGACCTGACCT-39, reverse 59-TGCTGTAGCCAAAT ation and/or expression of genes involved in the regula- TCGTTG-3) and SYBR Green PCR Master Mix (Applied Bio- tion of energy homeostasis (which may influence both systems, Foster City, CA). PCR reactions were performed us- early growth and later diabetes risk) differ between offspring ing a 7500 Real-Time PCR System (Applied Biosystems) by born appropriate-for-gestational-age (AGA) or SGA after an mixing 1 mLofcDNA(20ng)with24mL of reaction mixture uncomplicated, term, singleton pregnancy. (14 mL23 SYBR Green I Master Mix buffer), 2 mLforward primer (2.5 mmol/L), 2 mL reverse primer (2.5 mmol/L), and RESEARCH DESIGN AND METHODS 6 mL of nuclease-free water. Relative expression was then Study Population calculated according to the 2-DCt method (14). The study cohort consisted of 51 mother-placenta-new- The details regarding cord blood and placenta collec- born trios, with postnatal follow-up (Supplementary Fig. tion, DNA extraction and modification, microarray data 1). Thirty infants were born AGA (17 girls, 13 boys) and preprocessing, validation by bisulfite pyrosequencing, RNA 21 SGA (9 girls, 12 boys). The inclusion and exclusion extraction, and retrotranscription, as well as the assays and criteria are detailed in Supplementary Data. neonatal body composition assessment procedures, are pro- Maternal age at conception, parity, and height, as well as vided in the Supplementary Data. pregestational weight and BMI [weight (kg)/height (m2)], were retrieved from clinical records. Gestational age was cal- Statistics and Ethics culated from last menses and confirmed by first-trimester Statistical analyses were performed using SPSS Statistics ultrasound (;10 weeks). 23.0 (IBM Corp., Armonk, NY). Unpaired t test was used to The infant’s weight and length were measured by the study differences between AGA and SGA subgroups. Corre- same investigator (G.S.) at birth and at the postnatal age lation and stepwise multiple regression analysis were used of approximately 2 weeks. Weight was measured with a to study how methylation status and expression levels in beam balance (Seca, Hamburg, Germany) and length with placenta and cord blood were associated with auxological a length board, using the mean of three measurements. and body composition parameters. Covariance analysis was used to adjust for sex, gestational age, type of delivery, and DNA Methylation Microarray in Placenta pregestational BMI. The level of significance was set at P , fi DNA methylation pro ling was performed in eight AGA 0.05. and eight SGA samples with the Agilent DNA Methylation The study was approved by the Institutional Review Board array (ID 049738, Agilent Technologies), which examines of Hospital Sant Joan de Déu at the University of Barcelona. 27,800 highly informative CpG sites located within the Written informed consent was obtained before delivery. proximal promoter regions of 14,475 genes. Nearly 100% of these CpG sites were localized within CpG islands. The process for isolating methylated DNA from purified DNA RESULTS samples, as well as labeling and hybridization to the Maternal and Offspring Characteristics Human DNA Methylation Array, was conducted following Table 1 summarizes the anthropometric parameters in the manufacturer’s protocol (Agilent Microarray Analysis the mothers and newborns by birth weight subgroup. of Methylated DNA Immunoprecipitation version 1.1, The delivery rate by cesarean section was not different Agilent Technologies). Briefly, 5 mg of purified DNA was between the AGA and SGA subgroups (13% vs. 19%, re- sonicated in PBS; DNA fragments were run in a 1.5% spectively). SGA infants displayed lower circulating levels agarose gel and ranged in size from 200 to 1,000 base pairs. of insulin and IGF-I in cord blood and less fat and lean Enrichment of methylated regions was performed using an mass at age 2 weeks, as expected, while their mothers antibody against 5-methylcytosine. Enriched and unen- were shorter and had a lower pregestational weight and riched DNA samples were labeled with Cy3 and Cy5, res- BMI (14). pectively, and hybridized in the microarray. The microarray Gene Ontology and Functional Pathway Analysis chip was then washed and immediately scanned using a We identified 409 genes differentially methylated in SGA microarray scanner (Model G2505C, Agilent Technologies). newborns (false discovery rate , 0.1) (Supplementary Gene Expression Analysis in Placenta and Cord Blood Table 1). The gene ontology analysis disclosed that most Steady-state mRNA levels of GPR120, ATG2B, NKX6.1, of them were involved in the regulation of metabolic and SLC13A5, as well as the housekeeping gene GAPDH, processes, DNA binding and transcription,
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