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Genetic and epigenetic regulation of gene expression in fetal and adult human livers
BACKGROUND: The liver plays a central role in the maintenance of homeostasis and health in general. However, there is substantial inter-individual variation in hepatic gene expression, and although numerous genetic factors have been identified, less is known about the epigenetic factors. RESULTS: By...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287518/ https://www.ncbi.nlm.nih.gov/pubmed/25282492 http://dx.doi.org/10.1186/1471-2164-15-860 |
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author | Bonder, Marc Jan Kasela, Silva Kals, Mart Tamm, Riin Lokk, Kaie Barragan, Isabel Buurman, Wim A Deelen, Patrick Greve, Jan-Willem Ivanov, Maxim Rensen, Sander S van Vliet-Ostaptchouk, Jana V Wolfs, Marcel G Fu, Jingyuan Hofker, Marten H Wijmenga, Cisca Zhernakova, Alexandra Ingelman-Sundberg, Magnus Franke, Lude Milani, Lili |
author_facet | Bonder, Marc Jan Kasela, Silva Kals, Mart Tamm, Riin Lokk, Kaie Barragan, Isabel Buurman, Wim A Deelen, Patrick Greve, Jan-Willem Ivanov, Maxim Rensen, Sander S van Vliet-Ostaptchouk, Jana V Wolfs, Marcel G Fu, Jingyuan Hofker, Marten H Wijmenga, Cisca Zhernakova, Alexandra Ingelman-Sundberg, Magnus Franke, Lude Milani, Lili |
author_sort | Bonder, Marc Jan |
collection | PubMed |
description | BACKGROUND: The liver plays a central role in the maintenance of homeostasis and health in general. However, there is substantial inter-individual variation in hepatic gene expression, and although numerous genetic factors have been identified, less is known about the epigenetic factors. RESULTS: By analyzing the methylomes and transcriptomes of 14 fetal and 181 adult livers, we identified 657 differentially methylated genes with adult-specific expression, these genes were enriched for transcription factor binding sites of HNF1A and HNF4A. We also identified 1,000 genes specific to fetal liver, which were enriched for GATA1, STAT5A, STAT5B and YY1 binding sites. We saw strong liver-specific effects of single nucleotide polymorphisms on both methylation levels (28,447 unique CpG sites (meQTL)) and gene expression levels (526 unique genes (eQTL)), at a false discovery rate (FDR) < 0.05. Of the 526 unique eQTL associated genes, 293 correlated significantly not only with genetic variation but also with methylation levels. The tissue-specificities of these associations were analyzed in muscle, subcutaneous adipose tissue and visceral adipose tissue. We observed that meQTL were more stable between tissues than eQTL and a very strong tissue-specificity for the identified associations between CpG methylation and gene expression. CONCLUSIONS: Our analyses generated a comprehensive resource of factors involved in the regulation of hepatic gene expression, and allowed us to estimate the proportion of variation in gene expression that could be attributed to genetic and epigenetic variation, both crucial to understanding differences in drug response and the etiology of liver diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2164-15-860) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4287518 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-42875182015-01-09 Genetic and epigenetic regulation of gene expression in fetal and adult human livers Bonder, Marc Jan Kasela, Silva Kals, Mart Tamm, Riin Lokk, Kaie Barragan, Isabel Buurman, Wim A Deelen, Patrick Greve, Jan-Willem Ivanov, Maxim Rensen, Sander S van Vliet-Ostaptchouk, Jana V Wolfs, Marcel G Fu, Jingyuan Hofker, Marten H Wijmenga, Cisca Zhernakova, Alexandra Ingelman-Sundberg, Magnus Franke, Lude Milani, Lili BMC Genomics Research Article BACKGROUND: The liver plays a central role in the maintenance of homeostasis and health in general. However, there is substantial inter-individual variation in hepatic gene expression, and although numerous genetic factors have been identified, less is known about the epigenetic factors. RESULTS: By analyzing the methylomes and transcriptomes of 14 fetal and 181 adult livers, we identified 657 differentially methylated genes with adult-specific expression, these genes were enriched for transcription factor binding sites of HNF1A and HNF4A. We also identified 1,000 genes specific to fetal liver, which were enriched for GATA1, STAT5A, STAT5B and YY1 binding sites. We saw strong liver-specific effects of single nucleotide polymorphisms on both methylation levels (28,447 unique CpG sites (meQTL)) and gene expression levels (526 unique genes (eQTL)), at a false discovery rate (FDR) < 0.05. Of the 526 unique eQTL associated genes, 293 correlated significantly not only with genetic variation but also with methylation levels. The tissue-specificities of these associations were analyzed in muscle, subcutaneous adipose tissue and visceral adipose tissue. We observed that meQTL were more stable between tissues than eQTL and a very strong tissue-specificity for the identified associations between CpG methylation and gene expression. CONCLUSIONS: Our analyses generated a comprehensive resource of factors involved in the regulation of hepatic gene expression, and allowed us to estimate the proportion of variation in gene expression that could be attributed to genetic and epigenetic variation, both crucial to understanding differences in drug response and the etiology of liver diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2164-15-860) contains supplementary material, which is available to authorized users. BioMed Central 2014-10-04 /pmc/articles/PMC4287518/ /pubmed/25282492 http://dx.doi.org/10.1186/1471-2164-15-860 Text en © Bonder et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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 Article Bonder, Marc Jan Kasela, Silva Kals, Mart Tamm, Riin Lokk, Kaie Barragan, Isabel Buurman, Wim A Deelen, Patrick Greve, Jan-Willem Ivanov, Maxim Rensen, Sander S van Vliet-Ostaptchouk, Jana V Wolfs, Marcel G Fu, Jingyuan Hofker, Marten H Wijmenga, Cisca Zhernakova, Alexandra Ingelman-Sundberg, Magnus Franke, Lude Milani, Lili Genetic and epigenetic regulation of gene expression in fetal and adult human livers |
title | Genetic and epigenetic regulation of gene expression in fetal and adult human livers |
title_full | Genetic and epigenetic regulation of gene expression in fetal and adult human livers |
title_fullStr | Genetic and epigenetic regulation of gene expression in fetal and adult human livers |
title_full_unstemmed | Genetic and epigenetic regulation of gene expression in fetal and adult human livers |
title_short | Genetic and epigenetic regulation of gene expression in fetal and adult human livers |
title_sort | genetic and epigenetic regulation of gene expression in fetal and adult human livers |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287518/ https://www.ncbi.nlm.nih.gov/pubmed/25282492 http://dx.doi.org/10.1186/1471-2164-15-860 |
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