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Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes

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Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes

dc.contributor.author	Pérez, Raúl F.
dc.contributor.author	Santamarina, Pablo
dc.contributor.author	Tejedor, Juan Ramón
dc.contributor.author	Urdinguio, Rocio G.
dc.contributor.author	Álvarez Pitti, Julio Carlos
dc.contributor.author	Redon, Pau
dc.contributor.author	Fernández, Agustin F.
dc.contributor.author	Fraga, Mario F.
dc.contributor.author	Lurbe i Ferrer, Empar
dc.date.accessioned	2019-10-03T11:20:44Z
dc.date.available	2019-10-03T11:20:44Z
dc.date.issued	2019
dc.identifier.citation	Pérez, Raúl F Santamarina, Pablo Tejedor, Juan Ramón Urdinguio, Rocio G. Álvarez Pitti, Julio Carlos Redon, Pau Fernández, Agustin F. Fraga, Mario F. Lurbe i Ferrer, Empar 2019 Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes. Journal Of Translational Medicine 17 1 15 15
dc.identifier.uri	https://hdl.handle.net/10550/71649
dc.description.abstract	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.
dc.language.iso	cat
dc.relation.ispartof	Journal of Translational Medicine, 2019, vol. 17, num. 1, p. 15-15
dc.subject	ADN
dc.title	Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes
dc.type	journal article	es_ES
dc.date.updated	2019-10-03T11:20:44Z
dc.identifier.doi	10.1186/s12967-018-1751-9
dc.identifier.idgrec	134650
dc.rights.accessRights	open access	es_ES