Developmental Stage-Specific IGF1 Gene Methylation in Infants with Intrauterine Growth Restriction

Background: IGF1 is a key molecule in the regulation of growth and metabolism. Low IGF1 secretion is known to cause growth restriction in childhood, as well as deregulated lipid metabolism, cardiovascular disease, and diabetes in adulthood. The IGF1 gene P2 promoter is highly methylated, resulting in low secretion of IGF1 in small infants and children. However, it is unknown when this methylation occurs. The aim of study was to clarify the point when this epigenetic program occurs during intrauterine development. Methods: We analyzed 57 preterm infants born before 32 weeks of gestation, including 20 intrauterine growth restriction (IUGR) infants whose birth weights were lower than −2SD calculated by the Japanese datasets. We extracted genomic DNA from whole blood at birth; methylation of the IGF1 P2 promoter was analyzed by the bisulfite amplicon method using the MiSeq platform. Findings: In contrast to term infants and children, IGF1 promoter methylation levels were significantly reduced in infants with IUGR. Interpretation: These findings indicated that the IGF1 gene is epigenetically activated before 32 weeks of gestation in infants with IUGR, and that the activated gene may become suppressed after this time point. This study may provide new insights to prevent the onset of adult diseases and to aid in nutritional management for preterm birth infants in neonatal intensive care units. Funding Statement: This work was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-Supported Program for the Strategic Research Foundation at Private Universities, 2015-2019, Japan (M.K.) and by Grants-in-Aid for General Scientific Research, No. 17k16309, Japan (N.I.). Declaration of Interests:The authors declare no competing interests. Ethics Approval Statement: This study was approved by the Juntendo University Ethics Committee and conducted in accordance with the principles of the Declaration of Helsinki.