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

Yuko Yamaguchi, Chiharu Tayama, Junko Tomikawa, Rina Akaishi, Hiromi Kamura, Kentaro Matsuoka, Norio Wake, Hisanori Minakami, Kiyoko Kato, Takahiro Yamada, Kazuhiko Nakabayashi, Kenichiro Hata

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number113
JournalClinical Epigenetics
Volume11
Issue number1
DOIs
Publication statusPublished - Aug 1 2019

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Pregnancy Induced Hypertension
Pregnancy Complications
Placenta
Fetal Development
Pregnancy
Methylation
Silver-Russell Syndrome
Alleles
Growth Disorders
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
DNA Methylation
Fetal Blood
Genes
Mothers

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

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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; Tayama, Chiharu; Tomikawa, Junko; Akaishi, Rina; Kamura, Hiromi; Matsuoka, Kentaro; Wake, Norio; Minakami, Hisanori; Kato, Kiyoko; Yamada, Takahiro; Nakabayashi, Kazuhiko; Hata, Kenichiro.

In: Clinical Epigenetics, Vol. 11, No. 1, 113, 01.08.2019.

Research output: Contribution to journalArticle

Yamaguchi, Y, Tayama, C, Tomikawa, J, Akaishi, R, Kamura, H, Matsuoka, K, Wake, N, Minakami, H, Kato, K, Yamada, T, Nakabayashi, K & Hata, K 2019, 'Placenta-specific epimutation at H19-DMR among common pregnancy complications: Its frequency and effect on the expression patterns of H19 and IGF2', Clinical Epigenetics, vol. 11, no. 1, 113. https://doi.org/10.1186/s13148-019-0712-3
Yamaguchi, Yuko ; Tayama, Chiharu ; Tomikawa, Junko ; Akaishi, Rina ; Kamura, Hiromi ; Matsuoka, Kentaro ; Wake, Norio ; Minakami, Hisanori ; Kato, Kiyoko ; Yamada, Takahiro ; Nakabayashi, Kazuhiko ; Hata, Kenichiro. / Placenta-specific epimutation at H19-DMR among common pregnancy complications : Its frequency and effect on the expression patterns of H19 and IGF2. In: Clinical Epigenetics. 2019 ; Vol. 11, No. 1.
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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.",
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T1 - Placenta-specific epimutation at H19-DMR among common pregnancy complications

T2 - Its frequency and effect on the expression patterns of H19 and IGF2

AU - Yamaguchi, Yuko

AU - Tayama, Chiharu

AU - Tomikawa, Junko

AU - Akaishi, Rina

AU - Kamura, Hiromi

AU - Matsuoka, Kentaro

AU - Wake, Norio

AU - Minakami, Hisanori

AU - Kato, Kiyoko

AU - Yamada, Takahiro

AU - Nakabayashi, Kazuhiko

AU - Hata, Kenichiro

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

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