title: Genetic and epigenetic regulation of gene expression in fetal and adult human livers.
abstract: 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.
authors.forename: Marc Jan
authors.initials: MJ
authors.lastname: Bonder
authors.forename: Silva
authors.initials: S
authors.lastname: Kasela
authors.forename: Mart
authors.initials: M
authors.lastname: Kals
authors.forename: Riin
authors.initials: R
authors.lastname: Tamm
authors.forename: Kaie
authors.initials: K
authors.lastname: Lokk
authors.forename: Isabel
authors.initials: I
authors.lastname: Barragan
authors.forename: Wim A
authors.initials: WA
authors.lastname: Buurman
authors.forename: Patrick
authors.initials: P
authors.lastname: Deelen
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Greve
authors.forename: Maxim
authors.initials: M
authors.lastname: Ivanov
authors.forename: Sander S
authors.initials: SS
authors.lastname: Rensen
authors.forename: Jana V
authors.initials: JV
authors.lastname: van Vliet-Ostaptchouk
authors.forename: Marcel G
authors.initials: MG
authors.lastname: Wolfs
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fu
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.forename: Magnus
authors.initials: M
authors.lastname: Ingelman-Sundberg
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Hanzeplein 1, 9700 RB Groningen, the Netherlands. lude@ludesign.nl.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.forename: Lili
authors.initials: L
authors.lastname: Milani
mesh_terms: D000328:Adult; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics; D005333:Fetus / Q000196:embryology / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008099:Liver / Q000254:growth & development* / Q000378:metabolism*; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics