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

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...

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Autores principales:	Nora Fernandez-Jimenez, Koldo Garcia-Etxebarria, Leticia Plaza-Izurieta, Irati Romero-Garmendia, Amaia Jauregi-Miguel, Maria Legarda, Szilvia Ecsedi, Ainara Castellanos-Rubio, Vincent Cahais, Cyrille Cuenin, Davide Degli Esposti, Iñaki Irastorza, Hector Hernandez-Vargas, Zdenko Herceg, Jose Ramon Bilbao
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/49108c83776145ee885324a210722b7d
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spelling	oai:doaj.org-article:49108c83776145ee885324a210722b7d2021-12-02T16:08:43ZThe methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region10.1038/s41598-018-37746-62045-2322https://doaj.org/article/49108c83776145ee885324a210722b7d2019-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-37746-6https://doaj.org/toc/2045-2322Abstract 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.Nora Fernandez-JimenezKoldo Garcia-EtxebarriaLeticia Plaza-IzurietaIrati Romero-GarmendiaAmaia Jauregi-MiguelMaria LegardaSzilvia EcsediAinara Castellanos-RubioVincent CahaisCyrille CueninDavide Degli EspostiIñaki IrastorzaHector Hernandez-VargasZdenko HercegJose Ramon BilbaoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-13 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nora Fernandez-Jimenez Koldo Garcia-Etxebarria Leticia Plaza-Izurieta Irati Romero-Garmendia Amaia Jauregi-Miguel Maria Legarda Szilvia Ecsedi Ainara Castellanos-Rubio Vincent Cahais Cyrille Cuenin Davide Degli Esposti Iñaki Irastorza Hector Hernandez-Vargas Zdenko Herceg Jose Ramon Bilbao The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region
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.
format	article
author	Nora Fernandez-Jimenez Koldo Garcia-Etxebarria Leticia Plaza-Izurieta Irati Romero-Garmendia Amaia Jauregi-Miguel Maria Legarda Szilvia Ecsedi Ainara Castellanos-Rubio Vincent Cahais Cyrille Cuenin Davide Degli Esposti Iñaki Irastorza Hector Hernandez-Vargas Zdenko Herceg Jose Ramon Bilbao
author_facet	Nora Fernandez-Jimenez Koldo Garcia-Etxebarria Leticia Plaza-Izurieta Irati Romero-Garmendia Amaia Jauregi-Miguel Maria Legarda Szilvia Ecsedi Ainara Castellanos-Rubio Vincent Cahais Cyrille Cuenin Davide Degli Esposti Iñaki Irastorza Hector Hernandez-Vargas Zdenko Herceg Jose Ramon Bilbao
author_sort	Nora Fernandez-Jimenez
title	The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region
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	methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the hla region
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/49108c83776145ee885324a210722b7d
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The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region

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