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Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes
BACKGROUND: Early life is a period of drastic epigenetic remodeling in which the epigenome is especially sensitive to extrinsic and intrinsic influence. However, the epigenome-wide dynamics of the DNA methylation changes that occur during this period have not been sufficiently characterized in longi...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327427/ https://www.ncbi.nlm.nih.gov/pubmed/30626398 http://dx.doi.org/10.1186/s12967-018-1751-9 |
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author | Pérez, Raúl F. Santamarina, Pablo Tejedor, Juan Ramón Urdinguio, Rocío G. Álvarez-Pitti, Julio Redon, Pau Fernández, Agustín F. Fraga, Mario F. Lurbe, Empar |
author_facet | Pérez, Raúl F. Santamarina, Pablo Tejedor, Juan Ramón Urdinguio, Rocío G. Álvarez-Pitti, Julio Redon, Pau Fernández, Agustín F. Fraga, Mario F. Lurbe, Empar |
author_sort | Pérez, Raúl F. |
collection | PubMed |
description | BACKGROUND: Early life is a period of drastic epigenetic remodeling in which the epigenome is especially sensitive to extrinsic and intrinsic influence. However, the epigenome-wide dynamics of the DNA methylation changes that occur during this period have not been sufficiently characterized in longitudinal studies. METHODS: To this end, we studied the DNA methylation status of more than 750,000 CpG sites using Illumina MethylationEPIC arrays on 33 paired blood samples from 11 subjects at birth and at 5 and 10 years of age, then characterized the chromatin context associated with these loci by integrating our data with histone, chromatin-state and enhancer-element external datasets, and, finally, validated our results through bisulfite pyrosequencing in two independent longitudinal cohorts of 18 additional subjects. RESULTS: We found abundant DNA methylation changes (110,726 CpG sites) during the first lustrum of life, while far fewer alterations were observed in the subsequent 5 years (460 CpG sites). However, our analysis revealed persistent DNA methylation changes at 240 CpG sites, indicating that there are genomic locations of considerable epigenetic change beyond immediate birth. The chromatin context of hypermethylation changes was associated with repressive genomic locations and genes with developmental and cell signaling functions, while hypomethylation changes were linked to enhancer regions and genes with immunological and mRNA and protein metabolism functions. Significantly, our results show that genes that suffer simultaneous hyper- and hypomethylation are functionally distinct from exclusively hyper- or hypomethylated genes, and that enhancer-associated methylation is different in hyper- and hypomethylation scenarios, with hypomethylation being more associated to epigenetic changes at blood tissue-specific enhancer elements. CONCLUSIONS: These data show that epigenetic remodeling is dramatically reduced after the first 5 years of life. However, there are certain loci which continue to manifest DNA methylation changes, pointing towards a possible functionality beyond early development. Furthermore, our results deepen the understanding of the genomic context associated to hyper- or hypomethylation alterations during time, suggesting that hypomethylation of blood tissue-specific enhancer elements could be of importance in the establishment of functional states in blood tissue during early-life. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-018-1751-9) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6327427 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-63274272019-01-15 Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes Pérez, Raúl F. Santamarina, Pablo Tejedor, Juan Ramón Urdinguio, Rocío G. Álvarez-Pitti, Julio Redon, Pau Fernández, Agustín F. Fraga, Mario F. Lurbe, Empar J Transl Med Research BACKGROUND: Early life is a period of drastic epigenetic remodeling in which the epigenome is especially sensitive to extrinsic and intrinsic influence. However, the epigenome-wide dynamics of the DNA methylation changes that occur during this period have not been sufficiently characterized in longitudinal studies. METHODS: To this end, we studied the DNA methylation status of more than 750,000 CpG sites using Illumina MethylationEPIC arrays on 33 paired blood samples from 11 subjects at birth and at 5 and 10 years of age, then characterized the chromatin context associated with these loci by integrating our data with histone, chromatin-state and enhancer-element external datasets, and, finally, validated our results through bisulfite pyrosequencing in two independent longitudinal cohorts of 18 additional subjects. RESULTS: We found abundant DNA methylation changes (110,726 CpG sites) during the first lustrum of life, while far fewer alterations were observed in the subsequent 5 years (460 CpG sites). However, our analysis revealed persistent DNA methylation changes at 240 CpG sites, indicating that there are genomic locations of considerable epigenetic change beyond immediate birth. The chromatin context of hypermethylation changes was associated with repressive genomic locations and genes with developmental and cell signaling functions, while hypomethylation changes were linked to enhancer regions and genes with immunological and mRNA and protein metabolism functions. Significantly, our results show that genes that suffer simultaneous hyper- and hypomethylation are functionally distinct from exclusively hyper- or hypomethylated genes, and that enhancer-associated methylation is different in hyper- and hypomethylation scenarios, with hypomethylation being more associated to epigenetic changes at blood tissue-specific enhancer elements. CONCLUSIONS: These data show that epigenetic remodeling is dramatically reduced after the first 5 years of life. However, there are certain loci which continue to manifest DNA methylation changes, pointing towards a possible functionality beyond early development. Furthermore, our results deepen the understanding of the genomic context associated to hyper- or hypomethylation alterations during time, suggesting that hypomethylation of blood tissue-specific enhancer elements could be of importance in the establishment of functional states in blood tissue during early-life. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-018-1751-9) contains supplementary material, which is available to authorized users. BioMed Central 2019-01-09 /pmc/articles/PMC6327427/ /pubmed/30626398 http://dx.doi.org/10.1186/s12967-018-1751-9 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 Pérez, Raúl F. Santamarina, Pablo Tejedor, Juan Ramón Urdinguio, Rocío G. Álvarez-Pitti, Julio Redon, Pau Fernández, Agustín F. Fraga, Mario F. Lurbe, Empar Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes |
title | Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes |
title_full | Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes |
title_fullStr | Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes |
title_full_unstemmed | Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes |
title_short | Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes |
title_sort | longitudinal genome-wide dna methylation analysis uncovers persistent early-life dna methylation changes |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327427/ https://www.ncbi.nlm.nih.gov/pubmed/30626398 http://dx.doi.org/10.1186/s12967-018-1751-9 |
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