Differences in expression rather than methylation at placenta-specific imprinted loci is associated with intrauterine growth restriction

Monteagudo-Sánchez, Ana, Sánchez-Delgado, Marta, Mora, Jose Ramon Hernandez, Santamaría, Nuria Tubío, Gratacós, Eduard, Esteller, Manel, De Heredia, Miguel López, Nunes, Virgina, Choux, Cecile, Fauque, Patricia, De Nanclares, Guiomar Perez, Anton, Lauren, Elovitz, Michal A., Iglesias-Platas, Isabel and Monk, David (2019) Differences in expression rather than methylation at placenta-specific imprinted loci is associated with intrauterine growth restriction. Clinical Epigenetics, 11 (1). ISSN 1868-7075

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Background: Genome-wide studies have begun to link subtle variations in both allelic DNA methylation and parent-of-origin genetic effects with early development. Numerous reports have highlighted that the placenta plays a critical role in coordinating fetal growth, with many key functions regulated by genomic imprinting. With the recent description of wide-spread polymorphic placenta-specific imprinting, the molecular mechanisms leading to this curious polymorphic epigenetic phenomenon is unknown, as is their involvement in pregnancies complications. Results: Profiling of 35 ubiquitous and 112 placenta-specific imprinted differentially methylated regions (DMRs) using high-density methylation arrays and pyrosequencing revealed isolated aberrant methylation at ubiquitous DMRs as well as abundant hypomethylation at placenta-specific DMRs. Analysis of the underlying chromatin state revealed that the polymorphic nature is not only evident at the level of allelic methylation, but DMRs can also adopt an unusual epigenetic signature where the underlying histones are biallelically enrichment of H3K4 methylation, a modification normally mutually exclusive with DNA methylation. Quantitative expression analysis in placenta identified two genes, GPR1-AS1 and ZDBF2, that were differentially expressed between IUGRs and control samples after adjusting for clinical factors, revealing coordinated deregulation at the chromosome 2q33 imprinted locus. Conclusions: DNA methylation is less stable at placenta-specific imprinted DMRs compared to ubiquitous DMRs and contributes to privileged state of the placenta epigenome. IUGR-associated expression differences were identified for several imprinted transcripts independent of allelic methylation. Further work is required to determine if these differences are the cause IUGR or reflect unique adaption by the placenta to developmental stresses.

Item Type: Article
Additional Information: Funding Information: This study has been funded by Ministerio de Economía, Industria y Competitividad (MINECO), which is part of Agencia Estatal de Investigación (AEI), through the projects BFU2014-53093-R and BFU2017-85571-R (Co-funded by European Regional Development Fund; ERDF, a way to build Europe). We thank CERCA Programme / Generalitat de Catalunya for institutional support. A.M.S. is a recipient of a FPI PhD studentship from MINECO. The laboratory of M.A.E received funding from 2010 Vision Grant from the Preeclampsia Foundation (www.preeclampsia.org) and the Maternal and Child Health Research Fund at the University of Pennsylvania. Publisher Copyright: © 2019 The Author(s).
Uncontrolled Keywords: dna methylation,epigenetics,imprinting,placenta,molecular biology,genetics,developmental biology,genetics(clinical) ,/dk/atira/pure/subjectarea/asjc/1300/1312
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 03 Nov 2022 12:31
Last Modified: 03 Nov 2022 12:31
URI: https://ueaeprints.uea.ac.uk/id/eprint/89562
DOI: 10.1186/s13148-019-0630-4

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