The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region

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...

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Autores: Fernández Jiménez, Nora, García Etxebarria, Koldo, Plaza Izurieta, Leticia, Romero Garmendia, Irati, Jauregi Miguel, Amaia, Legarda Tamara, María, Ecsedi, Szilvia, Castellanos Rubio, Ainara, Cahais, Vincent, Cuenin, Cyrille, Degli Esposti, Davide, Irastorza Terradillos, Iñaki Xarles, Hernández Vargas, Héctor, Herceg, Zdenko, Bilbao Catalá, José Ramón
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/32163
Acceso en línea:http://hdl.handle.net/10810/32163
Access Level:acceso abierto
Palabra clave:inflammatory-bowel-disease
dna methylation
bioconductor package
wide analysis
cancer
epigenome
associations
lymphocytes
mechanisms
expression
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repository_id_str
dc.title.none.fl_str_mv The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region
title The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region
spellingShingle The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region
Fernández Jiménez, Nora
inflammatory-bowel-disease
dna methylation
bioconductor package
wide analysis
cancer
epigenome
associations
lymphocytes
mechanisms
expression
title_short The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region
title_full The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region
title_fullStr The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region
title_full_unstemmed The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region
title_sort The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region
dc.creator.none.fl_str_mv Fernández Jiménez, Nora
García Etxebarria, Koldo
Plaza Izurieta, Leticia
Romero Garmendia, Irati
Jauregi Miguel, Amaia
Legarda Tamara, María
Ecsedi, Szilvia
Castellanos Rubio, Ainara
Cahais, Vincent
Cuenin, Cyrille
Degli Esposti, Davide
Irastorza Terradillos, Iñaki Xarles
Hernández Vargas, Héctor
Herceg, Zdenko
Bilbao Catalá, José Ramón
author Fernández Jiménez, Nora
author_facet Fernández Jiménez, Nora
García Etxebarria, Koldo
Plaza Izurieta, Leticia
Romero Garmendia, Irati
Jauregi Miguel, Amaia
Legarda Tamara, María
Ecsedi, Szilvia
Castellanos Rubio, Ainara
Cahais, Vincent
Cuenin, Cyrille
Degli Esposti, Davide
Irastorza Terradillos, Iñaki Xarles
Hernández Vargas, Héctor
Herceg, Zdenko
Bilbao Catalá, José Ramón
author_role author
author2 García Etxebarria, Koldo
Plaza Izurieta, Leticia
Romero Garmendia, Irati
Jauregi Miguel, Amaia
Legarda Tamara, María
Ecsedi, Szilvia
Castellanos Rubio, Ainara
Cahais, Vincent
Cuenin, Cyrille
Degli Esposti, Davide
Irastorza Terradillos, Iñaki Xarles
Hernández Vargas, Héctor
Herceg, Zdenko
Bilbao Catalá, José Ramón
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv inflammatory-bowel-disease
dna methylation
bioconductor package
wide analysis
cancer
epigenome
associations
lymphocytes
mechanisms
expression
topic inflammatory-bowel-disease
dna methylation
bioconductor package
wide analysis
cancer
epigenome
associations
lymphocytes
mechanisms
expression
description 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/32163
url http://hdl.handle.net/10810/32163
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MINECO/ PI13/01201
info:eu-repo/grantAgreement/MINECO/PI16/00258
https://www.nature.com/articles/s41598-018-37746-6
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing
publisher.none.fl_str_mv Nature Publishing
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA regionFernández Jiménez, NoraGarcía Etxebarria, KoldoPlaza Izurieta, LeticiaRomero Garmendia, IratiJauregi Miguel, AmaiaLegarda Tamara, MaríaEcsedi, SzilviaCastellanos Rubio, AinaraCahais, VincentCuenin, CyrilleDegli Esposti, DavideIrastorza Terradillos, Iñaki XarlesHernández Vargas, HéctorHerceg, ZdenkoBilbao Catalá, José Ramóninflammatory-bowel-diseasedna methylationbioconductor packagewide analysiscancerepigenomeassociationslymphocytesmechanismsexpressionThe 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.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.Nature Publishing201920192019info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/32163reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MINECO/ PI13/01201info:eu-repo/grantAgreement/MINECO/PI16/00258https://www.nature.com/articles/s41598-018-37746-6info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/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/.Atribución 3.0 Españaoai:addi.ehu.eus:10810/321632026-06-18T09:23:17Z
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