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

Abstract

BackgroundThe 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.ResultsBy 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.ConclusionsOur 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 materialThe online version of this article (doi:10.1186/1471-2164-15-860) contains supplementary material, which is available to authorized users.

Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue

“…This is in agreement with studies of in vivo liver tissues (6,24,28,29). Furthermore, similar results of clusters of genes that are either not expressed or low in hPSC-HEP compared with primary hepa- tocytes are shown in (14), indicating remaining immature features of hPSC-HEP.…”

“…These pathways are well-known regulators of DE differentiation (60). The later differentiation stages (i.e., early and mature hPSC-HEP) were enriched for pathways and GO terms involved in typical hepatocyte functions such as lipid metabolism, complement and cholesterol regulators (statin pathway), which is well aligned with liver development (6,28). The late-stage clusters, starting from the hepatoblast stage and forward, were enriched for GO terms such as epithelial differentiation (implying the differentiation process of hepatoblasts, which are hepatic epithelial cells), bicellular tight junctions, vesicles, vacuoles, and regulation of ion transport involved in the clearance and transport of metabolites (40,45,46), in addition to pathways connected to important hepatocyte functions such as blood coagulation, complement system, lipid particle organization/ remodeling, and lipid metabolism (60).…”

Physiological Content and Intrinsic Activities of 10 Cytochrome P450 Isoforms in Human Normal Liver Microsomes

“…However, the intrinsic activity of P450 should be based on one P450 isoform level, because a substantial difference in the content of P450 isoforms exists in individual HLMs. Many factors could produce large variations in P450 activity, such as P450 protein content, genetic polymorphism, drug-drug interactions, and protein-protein interactions (Nebert and Russell, 2002;Nebert and Dalton, 2006;Bonder et al, 2014). The real effects of influential factors on P450 activity can be reflected in the intrinsic activity of P450.…”

Chromosome hydroxymethylation patterns in human zygotes and cleavage-stage embryos

“…In postimplantation development, the patterns of 5mC are established in a tissue-specific manner and are characterized by a relative stability and high heritability (Bird 2002, Byun et al 2009, Tolmacheva et al 2011, Bonder et al 2014. The correct DNA methylation patterns provide regulation of cell type-specific gene expression by affecting the capacity of DNA to interact with transcription factors and methyl-CpG-binding proteins (Doerfler 1981, Razin & Cedar 1991, Zou et al 2012).…”