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The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region
dc.contributor.author | Fernández Jiménez, Nora | |
dc.contributor.author | García Etxebarria, Koldo | |
dc.contributor.author | Plaza Izurieta, Leticia | |
dc.contributor.author | Romero Garmendia, Irati | |
dc.contributor.author | Jauregi Miguel, Amaia | |
dc.contributor.author | Legarda Tamara, María | |
dc.contributor.author | Ecsedi, Szilvia | |
dc.contributor.author | Castellanos Rubio, Ainara | |
dc.contributor.author | Cahais, Vincent | |
dc.contributor.author | Cuenin, Cyrille | |
dc.contributor.author | Degli Esposti, Davide | |
dc.contributor.author | Irastorza Terradillos, Iñaki Xarles | |
dc.contributor.author | Hernandez-Vargas, Hector | |
dc.contributor.author | Herceg, Zdenko | |
dc.contributor.author | Bilbao Catalá, José Ramón | |
dc.date.accessioned | 2019-03-26T13:19:30Z | |
dc.date.available | 2019-03-26T13:19:30Z | |
dc.date.issued | 2019-02-04 | |
dc.identifier.citation | Scientific Reports 9 : (2019) // Article ID 1298 | es_ES |
dc.identifier.issn | 2045-2322 | |
dc.identifier.uri | http://hdl.handle.net/10810/32163 | |
dc.description.abstract | The Human Leucocyte Antigen (HLA) locus and other DNA sequence variants identified in Genome-Wide Association (GWA) studies explain around 50% of the heritability of celiac disease (CD). However, the pathogenesis of CD could be driven by other layers of genomic information independent from sequence variation, such as DNA methylation, and it is possible that allele-specific methylation explains part of the SNP associations. Since the DNA methylation landscape is expected to be different among cell types, we analyzed the methylome of the epithelial and immune cell populations of duodenal biopsies in CD patients and controls separately. We found a cell type-specific methylation signature that includes genes mapping to the HLA region, namely TAP1 and HLA-B. We also performed Immunochip SNP genotyping of the same samples and interrogated the expression of some of the affected genes. Our analysis revealed that the epithelial methylome is characterized by the loss of CpG island (CGI) boundaries, often associated to altered gene expression, and by the increased variability of the methylation across the samples. The overlap between differentially methylated positions (DMPs) and CD-associated SNPs or variants contributing to methylation quantitative trait loci (mQTLs) is minimal. In contrast, there is a notable enrichment of mQTLs among the most significant CD-associated SNPs. Our results support the notion that DNA methylation alterations constitute a genotype-independent event and confirm its role in the HLA region (apart from the well-known, DQ allele-specific effect). Finally, we find that a fraction of the CD-associated variants could exert its phenotypic effect through DNA methylation. | es_ES |
dc.description.sponsorship | The authors thank the technical and human support provided by SGIker of the UPV/EHU and the Genomics Platform at the CIC bioGUNE. We also thank Dr Florence Le Calvez-Kelm and Mr Geoffroy Durand from the Genetic Cancer Susceptibility group (IARC, Lyon) for their help with the HM450 beadchip assays. The work was funded by ISCIII Research Project Grants PI13/01201 and PI16/00258, cofunded by the European Union ERDF/ESF "A way to make Europe" co-financed by the Spanish Ministry of Economy and Competitiveness -http://www.mineco.gob.es/-and by the European Union ERDF/ESF "A way to make Europe" and project 2011/111034 from the Basque Department of Health -http://www.euskadi.eus/gobierno-vasco/departamento-salud/inicio/-to J.R.B. N.F.J. was supported by an IARC Postodctoral Fellowship (FP7 Marie Curie Actions-People-COFUND) and a Postdoctoral Fellowship from the Basque Department of Education -http://training.iarc.fr/en/fellowships/postdoc.php-.I.R.G.and A.J.M. are supported by Predoctoral Fellowship grants from the UPV/EHU and the Basque Department of Education -http://www.euskadi.eus/gobierno-vasco/departamento-educacion/-, respectively. S.E. was supported by the abovementioned IARC Postdoctoral Fellowship program. ACR is an Ikerbasque Research Fellow -http://www.ikerbasque.net/-.The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data nor in writing the manuscript. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Nature Publishing | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/ PI13/01201 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/PI16/00258 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.subject | inflammatory-bowel-disease | es_ES |
dc.subject | dna methylation | es_ES |
dc.subject | bioconductor package | es_ES |
dc.subject | wide analysis | es_ES |
dc.subject | cancer | es_ES |
dc.subject | epigenome | es_ES |
dc.subject | associations | es_ES |
dc.subject | lymphocytes | es_ES |
dc.subject | mechanisms | es_ES |
dc.subject | expression | es_ES |
dc.title | The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. | es_ES |
dc.rights.holder | Atribución 3.0 España | * |
dc.relation.publisherversion | https://www.nature.com/articles/s41598-018-37746-6 | es_ES |
dc.identifier.doi | 10.1038/s41598-018-37746-6 | |
dc.departamentoes | Genética, antropología física y fisiología animal | es_ES |
dc.departamentoeu | Genetika,antropologia fisikoa eta animalien fisiologia | es_ES |
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Bestelakorik adierazi ezean, itemaren baimena horrela deskribatzen da:This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.