Differences in expression rather than methylation at placenta-specific imprinted loci is associated with intrauterine growth restriction
Por:
Monteagudo-Sánchez A, Sánchez-Delgado M, Hernandez-Mora JR, Tubío N, Gratacós E, Esteller M, López M, Nunes V, Choux C, Fauque P, Perez-de-Nanclares G, Anton L, Elovitz MA, Iglesias-Platas I and Monk D
Publicada:
26 feb 2019
Ahead of Print:
26 feb 2019
Resumen:
BackgroundGenome-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.ResultsProfiling 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.ConclusionsDNA 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.
Filiaciones:
Monteagudo-Sánchez A:
Imprinting and Cancer Group, Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute - IDIBELL, Av. Gran Via de L'Hospotalet 199-203, 08907 L'Hospitalet de Llobregat, Barcelona, Spain
Sánchez-Delgado M:
Imprinting and Cancer Group, Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute - IDIBELL, Av. Gran Via de L'Hospotalet 199-203, 08907 L'Hospitalet de Llobregat, Barcelona, Spain
Hernandez-Mora JR:
Imprinting and Cancer Group, Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute - IDIBELL, Av. Gran Via de L'Hospotalet 199-203, 08907 L'Hospitalet de Llobregat, Barcelona, Spain
Tubío N:
Imprinting and Cancer Group, Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute - IDIBELL, Av. Gran Via de L'Hospotalet 199-203, 08907 L'Hospitalet de Llobregat, Barcelona, Spain
Leibniz Institute on Aging, Jena, Germany
Gratacós E:
Fetal I+D Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine, Hospital Clínic and Hospital Sant Joan de Déu, Barcelona, Spain
Esteller M:
Cancer Epigenetics group, Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute - IDIBELL, Gran via, L'Hospitalet de Llobregat, Barcelona, Spain
Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
Institucio Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain
López M:
Human Molecular Genetics group, Genes, disease and Therapy Program, Bellvitge Biomedical Research Institute - IDIBELL, Av. Gran Via de L'Hospitalet 199-203, 08907, L'Hospitalet de Llobregat, Barcelona, Spain
Nunes V:
Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
Human Molecular Genetics group, Genes, disease and Therapy Program, Bellvitge Biomedical Research Institute - IDIBELL, Av. Gran Via de L'Hospitalet 199-203, 08907, L'Hospitalet de Llobregat, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
Choux C:
Université Bourgogne Franche-Comté - INSERM UMR1231, F-21000, Dijon, France
Fauque P:
Université Bourgogne Franche-Comté - INSERM UMR1231, F-21000, Dijon, France
Perez-de-Nanclares G:
(Epi) Genetics Laboratory, BioAraba National Health Institute, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Alava, Spain
Anton L:
Maternal and Child Health Research Program, Department of Obstetrics and Gynecology, Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, USA
Elovitz MA:
Maternal and Child Health Research Program, Department of Obstetrics and Gynecology, Center for Research on Reproduction and Women's Health, University of Pennsylvania, Philadelphia, USA
Iglesias-Platas I:
GReN (Grup de Reçerca en Neonatologia), BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine, Institut de Reçerca Sant Joan de Déu, Barcelona, Spain
Monk D:
Imprinting and Cancer Group, Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute - IDIBELL, Av. Gran Via de L'Hospotalet 199-203, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
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