Genetic and epigenetic regulation of gene expression in fetal and adult human livers

BMC Genomics

Lili Milani⁸  Lude Franke⁶  Magnus Ingelman-Sundberg⁷  Alexandra Zhernakova⁶  Cisca Wijmenga⁶  Marten H Hofker¹  Jingyuan Fu⁶  Marcel G Wolfs¹  Jana V van Vliet-Ostaptchouk⁹  Sander S Rensen²  Maxim Ivanov⁷  Jan-Willem Greve³  Patrick Deelen⁵  Wim A Buurman²  Isabel Barragan⁷  Kaie Lokk⁴  Riin Tamm⁴  Mart Kals^1,10  Silva Kasela⁴  Marc Jan Bonder⁶ 

[1] University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Molecular Genetics section, Groningen, the Netherlands;Department of Surgery, University Hospital Maastricht and Nutrition and Toxicology Research Institute (NUTRIM), Maastricht University, Maastricht, the Netherlands;Department of General Surgery, Atrium Medical Center Parkstad, Heerlen, the Netherlands;Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia;University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands;University of Groningen, University Medical Center Groningen, Department of Genetics, Hanzeplein 1, 9700 RB Groningen, the Netherlands;Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden;Estonian Genome Center, University of Tartu, Riia 23 B, 51010 Tartu, Estonia;University of Groningen, University Medical Center Groningen, Department of Endocrinology, Groningen, the Netherlands;Institute of Mathematical Statistics, University of Tartu, Tartu, Estonia

关键词: Liver;    HumanMethylation450;    Methylation;    Gene expression;    eQTM;    meQTL;    eQTL;   

Others  :  1136335
DOI  :  10.1186/1471-2164-15-860

 received in 2014-05-19, accepted in 2014-09-24,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Bonder et al.; licensee BioMed Central Ltd.

【 图 表 】

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