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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

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...

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Autores principales: Yamaguchi, Yuko, Tayama, Chiharu, Tomikawa, Junko, Akaishi, Rina, Kamura, Hiromi, Matsuoka, Kentaro, Wake, Norio, Minakami, Hisanori, Kato, Kiyoko, Yamada, Takahiro, Nakabayashi, Kazuhiko, Hata, Kenichiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676526/
https://www.ncbi.nlm.nih.gov/pubmed/31370882
http://dx.doi.org/10.1186/s13148-019-0712-3
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author Yamaguchi, Yuko
Tayama, Chiharu
Tomikawa, Junko
Akaishi, Rina
Kamura, Hiromi
Matsuoka, Kentaro
Wake, Norio
Minakami, Hisanori
Kato, Kiyoko
Yamada, Takahiro
Nakabayashi, Kazuhiko
Hata, Kenichiro
author_facet Yamaguchi, Yuko
Tayama, Chiharu
Tomikawa, Junko
Akaishi, Rina
Kamura, Hiromi
Matsuoka, Kentaro
Wake, Norio
Minakami, Hisanori
Kato, Kiyoko
Yamada, Takahiro
Nakabayashi, Kazuhiko
Hata, Kenichiro
author_sort Yamaguchi, Yuko
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13148-019-0712-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-66765262019-08-06 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 Clin Epigenetics Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13148-019-0712-3) contains supplementary material, which is available to authorized users. BioMed Central 2019-08-01 /pmc/articles/PMC6676526/ /pubmed/31370882 http://dx.doi.org/10.1186/s13148-019-0712-3 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
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
title Placenta-specific epimutation at H19-DMR among common pregnancy complications: its frequency and effect on the expression patterns of H19 and IGF2
title_full Placenta-specific epimutation at H19-DMR among common pregnancy complications: its frequency and effect on the expression patterns of H19 and IGF2
title_fullStr Placenta-specific epimutation at H19-DMR among common pregnancy complications: its frequency and effect on the expression patterns of H19 and IGF2
title_full_unstemmed Placenta-specific epimutation at H19-DMR among common pregnancy complications: its frequency and effect on the expression patterns of H19 and IGF2
title_short Placenta-specific epimutation at H19-DMR among common pregnancy complications: its frequency and effect on the expression patterns of H19 and IGF2
title_sort placenta-specific epimutation at h19-dmr among common pregnancy complications: its frequency and effect on the expression patterns of h19 and igf2
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676526/
https://www.ncbi.nlm.nih.gov/pubmed/31370882
http://dx.doi.org/10.1186/s13148-019-0712-3
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