Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2 (original) (raw)
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2020
Sex-specific transcription characterizes hundreds of genes in mouse liver, many implicated in sex-differential drug and lipid metabolism and disease susceptibility. While the regulation of liver sex differences by growth hormone-activated STAT5 is well established, little is known about autosomal genetic factors regulating the sex-specific liver transcriptome. Here we show, using genotyping and expression data from a large population of Diversity Outbred mice, that genetic factors work in tandem with growth hormone to control the individual variability of hundreds of sex-biased genes, including many lncRNA genes. Significant associations between single nucleotide polymorphisms and sex-specific gene expression were identified as expression quantitative trait loci (eQTLs), many of which showed strong sex-dependent associations. Remarkably, autosomal genetic modifiers of sex-specific genes were found to account for more than 200 instances of gain or loss of sex-specificity across eight...
Sex Differences in Liver Gene Expression in WT and SF-1 Knockout Mice
Slovenian Veterinary Research, 2018
Liver development and function are dependent on specific gene expression profile. Many genes in the liver are differentially expressed between females and males and these sex differences are thought to be at least partially influenced by sex specific patterns of growth hormone secretion. The aim of this study was to examine whether sex chromosomes contribute to sex differences in the liver gene expression. Expression of Cyp4a10, Cyp2u1, Cux2 and Hsd3b5, which are known to be differentially expressed between sexes in adulthood, were studied in WT and SF-1 knockout mice. Steroidogenic factor 1 knockout (SF-1 KO) mice that are born without gonads were used to determine whether there are any sex differences in the gene expression even in the absence of exposure to sex steroid hormones. Gonadectomised mice were also compared to gonadally intact mice and gene expression of studied genes was examined during estrous cycle in gonadally intact female mice. Higher expression of Cux2 and Cyp4a10 was detected in gonadally intact WT females in comparison to gonadally intact WT males and higher expression of Cyp2u1 and Hsd3b5 was detected in gonadally intact WT males in comparison to gonadally intact WT females. There were no sex differences in the expression of studied genes between WT gonadectomised and SF-1 KO mice. The results of our study therefore suggest that sex differences in the liver gene expression of the four studied genes are solely dependent on sex hormones and are not influenced by sex chromosome complement.
2018
Sex biased expression characterizes ~1,000 genes in mammalian liver, and impart sex differences in metabolism and disease susceptibility. The sex-dependent temporal patterns of pituitary growth hormone (GH) secretion, pulsatile in males and more continuous in females, are known to sex-differentially activate transcriptional regulators (TFs), leading to widespread sex-differences in the mouse liver transcriptome. This thesis elucidates sex-biased gene expression patterns in the following studies. Gene structures, expression patterns and species conservation are characterized for ~15,000 liverexpressed intergenic long noncoding RNAs (lncRNAs), many of which are novel. Analysis of intergenic lncRNA promoters revealed unexpected high conservation and significant enrichment of TF binding compared to protein-coding promoters. A subset of intergenic lncRNAs showed strong sex-specific and GH-dependent gene expression, and whose transcription was tightly correlated with the surrounding chromatin environment viii and TF binding patterns. The pervasive role of genetic factors to regulate sex-biased genes was revealed by analyzing livers with matched genotype and gene expression data from Diversity Outbred (DO) mice, an outbred population with high natural allelic variance derived from eight inbred strains. Significant associations between genetic variants and gene expression (eQTLs) were identified, including many eQTLs with a strong sex-biased association. Remarkably, a large fraction of these sex-biased eQTLs were linked to either gain or loss of sex-specific gene expression in the DO founder strain predicted to be regulated by the eQTL. Thus, genetic factors are a major contributor to the variability of sex-biased genes, which has important consequences related to the individual variability of liver phenotypes with known sex-differences. Natural genetic perturbations in DO mice were leveraged to identify candidate lncRNAs that may regulate hypophysectomy (hypox) responsiveness. Co-regulated protein-coding gene clusters were discovered based on gene expression correlations across DO mouse livers, many of which are enriched for distinct hypox response classes. LncRNAs whose expression showed unexpected significant negative correlation with protein-coding gene clusters enriched for genes of the opposite-sex bias and inverse hypox class were hypothesized to play negative regulatory role. In sum, these studies expand the characterization of the sex-biased hepatic transcriptome and reveal contributions of genetic factors to the regulation of sex bias in mammalian liver. .
Genomics, 2010
The human liver plays a vital role in meeting the body's metabolic needs and maintaining homeostasis. To address the molecular mechanisms of liver function, we integrated multiple gene expression datasets from microarray, MPSS, SAGE and EST platforms to generate a transcriptome atlas of the normal human liver. Our results show that 17396 genes are expressed in the human liver. 238 genes were identified as liver enrichment genes, involved in the functions of immune response and metabolic processes, from the MPSS and EST datasets. A comparative analysis of liver transcriptomes was performed in humans, mice and rats with microarray datasets shows that the expression profile of homologous genes remains significantly different between mouse/rat and human, suggesting a functional variance and regulation bias of genes expressed in the livers. The integrated liver transcriptome data should provide a valuable resource for the in-depth understanding of human liver biology and liver disease.
mRNA Levels in Control Rat Liver Display Strain-Specific, Hereditary, and AHR-Dependent Components
PLoS ONE, 2011
Rat is a major model organism in toxicogenomics and pharmacogenomics. Hepatic mRNA profiles after treatment with xenobiotic chemicals are used to predict and understand drug toxicity and mechanisms. Surprisingly, neither inter-and intra-strain variability of mRNA abundances in control rats nor the heritability of rat mRNA abundances yet been established. We address these issues by studying five populations: the popular Sprague-Dawley strain, sub-strains of Long-Evans and Wistar rats, and two lines derived from crosses between the Long-Evans and Wistar sub-strains. Using three independent techniques -variance analysis, linear modelling, and unsupervised pattern recognition -we characterize extensive intraand inter-strain variability in mRNA levels. We find that both sources of variability are non-random and are enriched for specific functional groups. Specific transcription-factor binding-sites are enriched in their promoter regions and these genes occur in ''islands'' scattered throughout the rat genome. Using the two lines generated by crossbreeding we tested heritability of hepatic mRNA levels: the majority of rat genes appear to exhibit directional genetics, with only a few interacting loci. Finally, a comparison of inter-strain heterogeneity between mouse and rat orthologs shows more heterogeneity in rats than mice; thus rat and mouse heterogeneity are uncorrelated. Our results establish that control hepatic mRNA levels are relatively homogeneous within rat strains but highly variable between strains. This variability may be related to increased activity of specific transcription-factors and has clear functional consequences. Future studies may take advantage of this phenomenon by surveying panels of rat strains.
Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and Humans
International Journal of Molecular Sciences
Multifactorial metabolic diseases, such as non-alcoholic fatty liver disease, are a major burden to modern societies, and frequently present with no clearly defined molecular biomarkers. Herein we used system medicine approaches to decipher signatures of liver fibrosis in mouse models with malfunction in genes from unrelated biological pathways: cholesterol synthesis—Cyp51, notch signaling—Rbpj, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling—Ikbkg, and unknown lysosomal pathway—Glmp. Enrichment analyses of Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome and TRANScription FACtor (TRANSFAC) databases complemented with genome-scale metabolic modeling revealed fibrotic signatures highly similar to liver pathologies in humans. The diverse genetic models of liver fibrosis exposed a common transcriptional program with activated estrogen receptor alpha (ERα) signaling, and a network of interactions between regulators of lipid metabolism and transcr...
Strain and gender modulate hepatic hepcidin 1 and 2 mRNA expression in mice
Blood Cells, Molecules, and Diseases, 2004
Hepcidin (HEPC) plays a key role in iron homeostasis and an abnormally low level of hepcidin mRNA has been reported in HFE-1 genetic hemochromatosis. Considering the well-known phenotypic variability of this disease, especially between men and women, it is important to define factors susceptible to modulate hepatic hepcidin expression and, consequently, to influence the development of iron overload in HFE-1 hemochromatosis. Therefore, our aim was to analyze the effects of strain and gender on hepatic hepcidin expression in the mouse. C57BL/6 and DBA/2 wild-type mice were included in this study. Liver and splenic iron contents were measured. Specific hepatic Hepc1 and Hepc2 mRNA levels were quantified using real-time reverse transcription polymerase chain reaction (RT-PCR). C57BL/6 mice expressed predominantly Hepc1 mRNA, whereas Hepc2 mRNA was the main form in DBA/2 mice. In both strains, females had higher levels of iron stores and Hepc mRNAs compared to males. Our results demonstrate that the expression of both hepcidin mRNAs varies according to strain and gender. They suggest that sex and genetic background, which are regulators of hepcidin expression, could play a role in the phenotypic expression of genetic hemochromatosis.
Strain dependent effects of sex hormones on hepatocarcinogenesis in mice
Carcinogenesis, 1996
In order to study the interaction of genetic and hormonal factors during murine hepatocarcinogenesis, we compared the number of liver tumors induced by treatment of 12day-old mice with AyV-dlethylnitrosamine (DEN) (0.05 (imol/g body wt) in intact mice and animals gonadectomized at 8 weeks of age from the three inbred strains, C3H/HeJ (C3H), C57BL/6J (B6), and C57BR/cdJ (BR). At 50 weeks of age, the mean liver tumor multiplicity in intact BR females was 28 ± 13, while that for intact female C3H and B6 mice was 1.4 ± 4.7 and 0.5 ± 1.0, respectively. In ovariectomized mice, the yield of liver tumors was ~8-fold higher than in intact C3H (103 ± 7.5) and B6 (4.1 ± 6.6) females. Only a slight increase (35 ± 14) was seen in ovariectomized BR females compared to intact BR females. Castration resulted in lower mean tumor multiplicities at 32 weeks of age in the males of all three strains. Intact male C3H, B6, and BR mice had mean liver tumor multiplicities of 61 ± 34, 7.4 ± 13, and 26 ± 18, respectively, while the mean tumor multiplicities in castrated C3H, B6, and BR mice were 24 ± 14, 0.5 ± 0.9, and 6.1^ ± 10 tumors per mouse, respectively. The apparent rate of growth of glucose-6-phosphatase-deficient, preneoplastic foci in DEN-treated BR females was significantly higher than in B6 females. The growth rates of hepatic foci in BR and B6 males were similar but foci in BR males were 5-fold more numerous than in B6 males. The high sensitivity of BR females may be due, at least in part, to the failure of ovarian hormones to inhibit the growth of preneoplastic foci and the subsequent development of liver tumors. Since BR males had a larger number of hepatic foci, it is likely that androgens increase the rate of focus formation in BR males.
Disruption of the c/ebpa Gene in Adult Mouse Liver
1997
The liver-enriched transcription factor C/EBPa has been implicated in the regulation of numerous liver- specific genes. It was previously reported that mice carrying a homozygous null mutation at the c/ebpa locus died as neonates due to the absence of hepatic glycogen and the resulting hypoglycemia. However, the lethal phenotype precluded further analysis of the role of C/EBPa in hepatic gene regulation in adult mice. To circumvent this problem, we constructed a conditional knockout allele of c/ebpa by using the Cre/loxP recom- bination system. Homozygous c/ebp-loxP mice, (c/ebpafl/fl; fl, flanked by loxP sites) were found to be indistin- guishable from their wild-type counterparts. However, when Cre recombinase was delivered to hepatocytes of adult c/ebpafl/fl mice by infusion of a recombinant adenovirus carrying the cre gene, more than 80% of the c/ebpafl/fl genes were deleted specifically in liver and C/EBPa expression was reduced by 90%. This condition resulted in a reduced leve...