The methylation levels of the H19 differentially methylated region in human umbilical cords reflect newborn parameters and changes by maternal environmental factors during early pregnancy

Abstract

H19 is a tumor-suppressor gene, and changes in the methylation of the H19-differential methylation region (H19-DMR) are related to human health. However, little is known about the factors that regulate the methylation levels of H19-DMR. Several recent studies have shown that maternal environmental factors during pregnancy, such as smoking, drinking, chemical exposure, and nutrient intake, can alter the methylation levels of several genes in fetal tissues. In this study, we examined the effects of maternal factors on changes in the methylation levels of H19-DMR in the human umbilical cord (UC), an extra-embryonic tissue. Participants from the Chiba study of Mother and Children's Health (C-MACH) were enrolled in this study. Genomic DNA was extracted from UC samples, and the methylation level of H19-DMR was evaluated by methylation-sensitive high resolution melting analysis. Individual maternal and paternal factors and clinical information for newborns at birth were examined using questionnaires prepared in the C-MACH study, a brief-type self-administered diet history questionnaire (BDHQ) during early pregnancy (gestational age of 12 weeks), and medical records. Univariate and multivariate logistic regression analyses indicated that reduced H19-DMR methylation (<50% methylation) in UC tissues was positively related to decreased head circumference in newborns [odds ratio (OR) =2.82; 95% confidence intervals (CI): 1.21-6.87; p=0.0183 and OR =2.51; 95% CI: 1.02-6.46; p=0.0499, respectively]. Moreover, multiple comparison test showed that H19-DMR methylation in UC tissues was significantly reduced in the low calorie group (intake of less than 1,000kcal/day; methylation level: 40.98%; 95% CI: 33.86-48.11) compared with that in the middle (1,000-1,999kcal/day; methylation level: 51.28%; 95% CI: 48.28-54.27) and high (≥2,000kcal/day; methylation level: 52.16%; 95% CI: 44.81-59.51) calorie groups (p=0.0054 and 0.047, respectively). In the subpopulations with low to moderate calorie intake (<2,000kcal/day), reduced H19-DMR methylation in UC tissues was significantly related to serum homocysteine concentration (OR =0.520; 95% CI: 0.285-0.875; p=0.019), maternal age (OR =1.22; 95% CI: 1.01-1.52; p=0.049), and serum folate levels (OR =0.917; 95% CI: 0.838-0.990; p=0.040). These data indicated that H19-DMR methylation levels in human UC tissues could be modulated by maternal factors during early pregnancy and may affect fetal and newborn growth.

Epigenome-wide scan identifies differentially methylated regions for lung cancer using pre-diagnostic peripheral blood

“…The direction of this association was unexpected since the overexpression of H19 LncRNA in lung tumor is often correlated with hypomethylation of the promoter region CpGs (Kondo et al 1995). H19 LncRNA belongs to a highly conserved imprinted gene cluster that plays important roles in embryonal development and growth control (Gabory et al 2010) and H19 region methylation has been found to be influenced by early life exposures, including maternal factors during pregnancy (Miyaso et al 2017), suggesting the possibility that external exposures could impact H19 methylation. Since the blood samples were drawn years before cancer diagnosis in this study, the methylation patterns we observed could be regions that are modulated early on in lung cancer development.…”

The Impact of Lifestyle, Diet and Physical Activity on Epigenetic Changes in the Offspring—A Systematic Review

“…Among the 16 studies included, 5 studies were RCTs [ 17 , 18 , 19 , 20 , 21 , 26 ] and 11 studies were cohort studies [ 3 , 4 , 6 , 12 , 13 , 14 , 16 , 22 , 23 , 24 , 25 ]. In total, 3617 mother–offspring pairs were included.…”

“…In total, 3617 mother–offspring pairs were included. Seven studies included participants from the USA [ 3 , 4 , 6 ], two from the United Kingdom (UK) [ 14 , 17 ], two from Ireland [ 18 , 19 ] and the rest of the studies included participants from China [ 24 ], Japan [ 16 ], Argentina [ 20 ], Denmark [ 21 ] and Scotland [ 13 ]. Two studies included data from the same RCT that investigated epigenetic changes at birth and at 5 years of age in offspring of mothers on a low glycemic index diet (Geraghty et al [ 19 ] and Geraghty et al [ 18 ], respectively).…”

Urine mercury levels correlate with DNA methylation of imprinting gene H19 in the sperm of reproductive-aged men

“…For instance, demethylation of H19 was associated with growth-related syndromes in human: hypomethylation of H19 being described in Silver-Russell Syndrome, characterized by severe intrauterine and postnatal growth retardation among other clinical features [ 33 ]. The study of samples from umbilical cord, reflecting maternal exposure to environmental adverse factors, indicated that reduced H19 -DMR methylation was related to decreased head circumference in newborns [ 34 ]. Whereas in a case-control study, examination of stillborn brain tissue from diagnosed NTDs revealed the hypermethylation of H19 compared with controls [ 35 ], which is not consistent with other studies.…”