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Placenta-specific epimutation at H19-DMR among common pregnancy complications: its frequency and effect on the expression patterns of H19 and IGF2.

ABSTRACT: BACKGROUND:H19 and IGF2 genes are imprinted and involved in regulating fetal and placental growth. The H19 differentially methylated region (DMR) is paternally methylated and maternally unmethylated and regulates the imprinted expression of H19 and IGF2. Epimutation at the H19-DMR in humans results in congenital growth disorders, Beckwith-Wiedemann and Silver-Russell syndromes, when erroneously its maternal allele becomes methylated and its paternal allele becomes unmethylated, respectively. Although H19 and IGF2 have been assessed for their involvement in pregnancy complications including fetal growth restriction (FGR) and pregnancy-induced hypertension (PIH)/hypertensive disorder of pregnancy (HDP) intensively in the last decade, it is still not established whether epimutation at the H19-DMR in the placenta results in pathogenic conditions in pregnancy. We aimed to assess the frequency of H19-DMR epimutation and its effects on the allelic expression patterns of H19 and IGF2 genes among normal and abnormal pregnancy cases. RESULTS:We enrolled two independently collected sets of placenta samples from normal pregnancies as controls and common pregnancy complications, FGR and PIH (HDP). The first set consisted of 39 controls and 140 FGR and/or PIH cases, and the second set consisted of 29 controls and 62 cases. For these samples, we initially screened for DNA methylation changes at H19-DMR and IGF2-DMRs by combined bisulfite restriction analysis, and further analyzed cases with methylation changes for their allelic methylation and expression patterns. We identified one case each of FGR and PIH showing hypomethylation of H19-DMR and IGF2-DMRs only in the placenta, but not in cord blood, from the first case/control set. For the PIH case, we were able to determine the allelic expression pattern of H19 to be biallelically expressed and the H19/IGF2 expression ratio to be highly elevated compared to controls. We also identified a PIH case with hypomethylation at H19-DMR and IGF2-DMRs in the placenta from the second case/control set. CONCLUSIONS:Placental epimutation at H19-DMR was observed among common pregnancy complication cases at the frequency of 1.5% (3 out of 202 cases examined), but not in 68 normal pregnancy cases examined. Alteration of H19/IGF2 expression patterns due to hypomethylation of H19-DMR may have been involved in the pathogenesis of pregnancy complications in these cases.

SUBMITTER: Yamaguchi Y

PROVIDER: S-EPMC6676526 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Placenta-specific epimutation at H19-DMR among common pregnancy complications: its frequency and effect on the expression patterns of H19 and IGF2.

Yamaguchi Yuko Y Tayama Chiharu C Tomikawa Junko J Akaishi Rina R Kamura Hiromi H Matsuoka Kentaro K Wake Norio N Minakami Hisanori H Kato Kiyoko K Yamada Takahiro T Nakabayashi Kazuhiko K Hata Kenichiro K

Clinical epigenetics 20190801 1

<h4>Background</h4>H19 and IGF2 genes are imprinted and involved in regulating fetal and placental growth. The H19 differentially methylated region (DMR) is paternally methylated and maternally unmethylated and regulates the imprinted expression of H19 and IGF2. Epimutation at the H19-DMR in humans results in congenital growth disorders, Beckwith-Wiedemann and Silver-Russell syndromes, when erroneously its maternal allele becomes methylated and its paternal allele becomes unmethylated, respectiv ...[more]

PMID: 31370882

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Project description:BackgroundAdherence to alternate Healthy Eating Index (AHEI), alternate Mediterranean diet (AMED), and Dietary Approaches to Stop Hypertension (DASH) has been linked to lower risks of chronic diseases. However, their associations with common pregnancy complications are unclear.ObjectivesThis study investigates the associations of AHEI, AMED, and DASH during periconception and pregnancy with common pregnancy complication risks.MethodsThe study included 1887 pregnant women from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons. Women responded to an FFQ at 8-13 gestational weeks, and they performed a 24-h dietary recall at 16-22 and 24-29 wk. Gestational diabetes (GDM), gestational hypertension, preeclampsia, and preterm delivery were ascertained using medical records.ResultsHealthier diet indicated by higher AHEI, AMED, and DASH scores was generally related to lower risks of pregnancy complications. Significant inverse associations were observed between AHEI score reported at 16-22 wk and GDM risk [adjusted RR (95% CI), highest (Q4) vs. lowest quartile (Q1): 0.32 (0.16, 0.66), P-trend = 0.002]; DASH score reported at both 8-13 [adjusted RR (95% CI), Q4 vs. Q1: 0.45 (0.17, 1.17), P-trend = 0.04] and 16-22 wk [adjusted RR (95% CI), Q4 vs. Q1: 0.19 (0.05, 0.65), P-trend = 0.01] and gestational hypertension risk; AHEI score reported at 24-29 wk and preeclampsia risk [adjusted RR (95% CI), Q4 vs. Q1: 0.31 (0.11, 0.87), P-trend = 0.03]; AMED score reported at 8-13 wk [adjusted RR (95% CI), Q4 vs. Q1: 0.50 (0.25, 1.01), P-trend = 0.03] and DASH score reported at 24-29 wk [adjusted RR (95% CI), Q4 vs. Q1: 0.50, (0.26, 0.96), P-trend = 0.03] and preterm delivery risk.ConclusionsAdherence to AHEI, AMED, or DASH during periconception and pregnancy was related to lower risks of GDM, gestational hypertension, preeclampsia, and preterm delivery.This study was registered at ClinicalTrials.gov as NCT00912132.

Project description:Imprinted genes play important roles in placental differentiation, growth and function, with profound effects on fetal development. In humans, H19 and IGF2 are imprinted, but imprinting of IGF2R remains controversial. The H19 non-coding RNA is a negative regulator of placental growth and altered placental imprinting of H19-IGF2 has been associated with pregnancy complications such as preeclampsia, which have been attributed to abnormal first trimester placentation. This suggests that changes in imprinting during the first trimester may precede aberrant placental morphogenesis. To better understand imprinting in the human placenta during early gestation, we quantified allele-specific expression for H19, IGF2 and IGF2R in first trimester (6-12 weeks gestation) and term placentae (37-42 weeks gestation) using pyrosequencing. Expression of IGF2R was biallelic, with a mean expression ratio of 49:51 (SD = 0.07), making transient imprinting unlikely. Expression from the repressed H19 alleles ranged from 1-25% and was higher (P<0.001) in first trimester (13.5 ± 8.2%) compared to term (3.4 ± 2.1%) placentae. Surprisingly, despite the known co-regulation of H19 and IGF2, little variation in expression of the repressed IGF2 alleles was observed (2.7 ± 2.0%). To identify regulatory regions that may be responsible for variation in H19 allelic expression, we quantified DNA methylation in the H19-IGF2 imprinting control region and H19 transcription start site (TSS). Unexpectedly, we found positive correlations (P<0.01) between DNA methylation levels and expression of the repressed H19 allele at 5 CpG's 2000 bp upstream of the H19 TSS. Additionally, DNA methylation was significantly higher (P<0.05) in first trimester compared with term placentae at 5 CpG's 39-523 bp upstream of the TSS, but was not correlated with H19 repressed allele expression. Our data suggest that variation in H19 imprinting may contribute to early programming of placental phenotype and illustrate the need for quantitative and robust methodologies to further elucidate the role of imprinted genes in normal and pathological placental development.

Project description:Data on the temporal dynamics of human placental gene expression is scarce. We have completed the first whole-genome profiling of human placental gene expression dynamics (GeneChips, Affymetrix®) from early to mid- gestation (10 samples; gestational weeks 5 to 18) and report 154 genes with considerable change in transcript levels (FDR P<0.1). Functional enrichment analysis revealed >200 GO categories that are statistically over-represented among 105 genes with dynamically increasing transcript levels. Analysis in an extended sample (n=43; gestational weeks 5 to 41) conformed a highly significant (FDR P<0.05) expressional peak in mid-gestation placenta for ten genes: BMP5, CCNG2, CDH11, FST, GATM, GPR183, ITGBL1, PLAGL1, SLC16A10, STC1. A central hypothesis of our study states that the aberrant expression of genes characteristic to mid-gestation placenta may contribute to affected fetal growth, maternal preeclampsia (PE) or gestational diabetes (GD). The gene STC1 coding for Stanniocalcin 1 (STC1) was identified with a sharp placental expressional peak in mid-gestation, increased mRNA levels at term and significantly elevated STC1 protein levels in post-partum maternal plasma in all pregnancy complications. The highest STC1 levels were identified in women, who developed simultaneously PE and delivered an SGA baby (median 731 vs 418 pg/ml in controls; P=0.001). CCNG2 and LYPD6 exhibited significantly increased placental mRNA expression and enhanced intensity of immunohistochemistry staining in placental sections all studied in GD and PE cases. Aberrant expression of mid-gestation specific genes in pregnancy complications at term indicates the importance of the fine-scale tuning of the temporal dynamics of transcription regulation in placenta. Observed significantly elevated plasma STC1 in complicated pregnancies warrants further investigations of its potential as a biomarker. Interestingly, a majority of genes with high expression in mid-gestation placenta have also been implicated in adult complex disease. This observation promotes a recently opened discussion on the role of placenta in developmental programming. 4 samples; this submission is extension of our earlier study (accession GSE22490).

Dataset Information

Placenta-specific epimutation at H19-DMR among common pregnancy complications: its frequency and effect on the expression patterns of H19 and IGF2.

Publications

Placenta-specific epimutation at H19-DMR among common pregnancy complications: its frequency and effect on the expression patterns of H19 and IGF2.

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