A comparative analysis of liver transcriptome suggests divergent liver function among human, mouse and rat (original) (raw)
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Uncovering the liver's role in immunity through RNA co-expression networks
Mammalian genome : official journal of the International Mammalian Genome Society, 2016
Gene co-expression analysis has proven to be a powerful tool for ascertaining the organization of gene products into networks that are important for organ function. An organ, such as the liver, engages in a multitude of functions important for the survival of humans, rats, and other animals; these liver functions include energy metabolism, metabolism of xenobiotics, immune system function, and hormonal homeostasis. With the availability of organ-specific transcriptomes, we can now examine the role of RNA transcripts (both protein-coding and non-coding) in these functions. A systems genetic approach for identifying and characterizing liver gene networks within a recombinant inbred panel of rats was used to identify genetically regulated transcriptional networks (modules). For these modules, biological consensus was found between functional enrichment analysis and publicly available phenotypic quantitative trait loci (QTL). In particular, the biological function of two liver modules c...
The human liver-specific proteome defined by transcriptomics and antibody-based profiling
The FASEB Journal, 2014
Human liver physiology and the genetic etiology of the liver diseases can potentially be elucidated through the identification of proteins with enriched expression in the liver. Here, we combined data from RNA sequencing (RNA-Seq) and antibody-based immunohistochemistry across all major human tissues to explore the human liver proteome with enriched expression, as well as the cell type-enriched expression in hepatocyte and bile duct cells. We identified in total 477 protein-coding genes with elevated expression in the liver: 179 genes have higher expression as compared to all the other analyzed tissues; 164 genes have elevated transcript levels in the liver shared with at least one other tissue type; and an additional 134 genes have a mild level of increased expression in the liver. We identified the precise localization of these proteins through antibodybased protein profiling and the subcellular localization of these proteins through immunofluorescent-based profiling. We also identified the biological processes and metabolic functions associated with these proteins, investigated their contribution in the occurrence of liver diseases, and identified potential targets for their treatment. Our study demonstrates the use of RNA-Seq and antibody-based immunohistochemistry for characterizing the human liver proteome, as well as the use of tissuespecific proteins in identification of novel drug targets and discovery of biomarkers.-Kampf, C., Mardinoglu, A., Fagerberg, L., Hallström, B. M., Edlund, K., Lundberg, E., Pontén, F., Nielsen, J., Uhlen, M. The human liver-specific proteome defined by transcriptomics and antibody-based profiling. FASEB J. 28, 000 -000 (2014). www.fasebj.org Key Words: immunohistochemistry ⅐ RNA sequencing ⅐ metabolism 1 These authors contributed equally to this work.
Genome-level analysis of genetic regulation of liver gene expression networks
Hepatology, 2007
The liver is the primary site for the metabolism of nutrients, drugs, and chemical agents. Although metabolic pathways are complex and tightly regulated, genetic variation among individuals, reflected in variations in gene expression levels, introduces complexity into research on liver disease. This study dissected genetic networks that control liver gene expression through the combination of large-scale quantitative mRNA expression analysis with genetic mapping in a reference population of BXD recombinant inbred mouse strains for which extensive singlenucleotide polymorphism, haplotype, and phenotypic data are publicly available. We profiled gene expression in livers of naive mice of both sexes from C57BL/6J, DBA/2J, B6D2F1, and 37 BXD strains using Agilent oligonucleotide microarrays. These data were used to map quantitative trait loci (QTLs) responsible for variations in the expression of about 19,000 transcripts. We identified polymorphic local and distant QTLs, including several loci that control the expression of large numbers of genes in liver, by comparing the physical transcript position with the location of the controlling QTL. Conclusion: The data are available through a public web-based resource (www.genenetwork.org) that allows custom data mining, identification of coregulated transcripts and correlated phenotypes, cross-tissue, and cross-species comparisons, as well as testing of a broad array of hypotheses. (HEPATOLOGY 2007;46:548-557.) Abbreviations: eQTL, expression quantitative trait locus; FDR, false discovery rate; Fmo3, flavin monooxygenase 3; GO, gene ontology; Hnf4g, hepatocyte nuclear factor 4-gamma; Il21r, interleukin 21 receptor; QTL, quantitative trait locus; LRS, likelihood ratio statistic; RI, recombinant inbred; SDP, strain distribution pattern; SNP, single-nucleotide polymorphism; TNF, tumor necrosis factor. From the
Hepatology Research, 2003
In the post-genome-sequencing era, full-length cDNA-sequence resources are extremely useful for functional analyses of genes. In addition, comprehensive gene profiling of human tissues at the mRNA level is also useful in understanding the molecular mechanisms of tissue-specific functions and disease pathogenesis. In this study, to obtain a wide variety of full-length cDNA clones derived from digestive tissues, numerous expressed sequence tags were generated from libraries enriched with full-length cDNAs. In total, 13 575 sequences were obtained from three cDNA libraries, which were constructed from tissues and cell lines of human liver, stomach, and pancreas. The integration of overlapping clones categorized the sequences into 5936 clusters (1666, 2746, and 2222 clusters in the liver, stomach, and pancreas, respectively). Of these, 1138 clones were scored as full-length cDNAs. Surprisingly, the redundant clones from all three tissues were assembled to show that only 101 genes (1.7% of the assembled 5936 genes) were shared. These results suggest that functional differences between tissues are probably related to their divergent gene expression profiles, and form a basis for understanding the molecular mechanisms underlying tissue-specific pathogenesis that are expressed in different organs. In addition, the full-length cDNAs obtained in this study should prove useful for future functional analyses of the genes expressed in digestive tissues. #
Global gene expression profile of normal and regenerating liver in young and old mice
AGE, 2015
The ability of the liver to regenerate and adjust its size after two/third partial hepatectomy (PH) is impaired in old rodents and humans. Here, we investigated by microarray analysis the expression pattern of hepatic genes in young and old untreated mice and the differences in gene expression profile following PH. Of the 10,237 messenger RNAs that had detectable expression, only 108 displayed a greater than 2-fold modification in gene expression levels between the two groups.
Mapping the Genetic Architecture of Gene Expression in Human Liver
PLOS Biology, 2008
Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process.
Hepatology, 2004
The goal of the current study was to provide complete coverage of the liver transcriptome with human probes corresponding to every gene expressed in embryonic, adult, and/or cancerous liver. We developed dedicated tools, namely, the Liverpool nylon array of complementary DNA (cDNA) probes for approximately 10,000 nonredundant genes and the LiverTools database. Inflammation-induced transcriptome changes were studied in liver tissue samples from patients with an acute systemic inflammation and from control subjects. One hundred and fifty-four messenger RNAs (mRNA) correlated statistically with the extent of inflammation. Of these, 134 mRNA samples were not associated previously with an acute-phase (AP) response. The hepatocyte origin and proinflammatory cytokine responsiveness of these mRNAs were confirmed by quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR) in cytokine-challenged hepatoma cells. The corresponding gene promoters were enriched in potential binding sites for inflammation-driven transcription factors in the liver. Some of the corresponding proteins may provide novel blood markers of clinical relevance. The mRNAs whose level is most correlated with the AP extent (P < .05) were enriched in intracellular signaling molecules, transcription factors, glycosylation enzymes, and up-regulated plasma proteins. In conclusion, the hepatocyte responded to the AP extent by fine tuning some mRNA levels, controlling most, if not all, intracellular events from early signaling to the final secretion of proteins involved in innate immunity. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/ jpages/0270-9139/suppmat/index.html).
Journal of Proteome Research, 2010
Herein, we report proteome and transcriptome profiles of the human adult liver and present an initial analysis. Overall, the human liver proteome (HLP) data set comprises 6788 identified proteins with at least two peptides matches at 95% confidence, including 3721 proteins newly identified in liver. The human liver transcriptome (HLT) data set consists of 11 205 expressed genes. The HLP is the largest proteome data set for a human organ and is the first direct association between a proteome and its transcriptome derived from the same sample. Although it is hard to approach complete coverage of the HLP currently, several conclusions based on this data set are clearly reached: (1) The 5816 proteinencoding genes (PEGs) represented by the HLP and the 11 104 PEGs represented in the HLT have been identified from 20 070 PEGs in IPI Human v3.07 and 19 478 PEGs in the integrated human transcriptome database, respectively. (2) The patterns of chromosomal distribution of the genes corresponding to the HLP are highly consistent with those of the HLT. Some chromosomal regions, such as 16p13. 3, 19q13.31, 19q13.42, and Xq28, exhibit particularly high densities of liver-specific genes, which perform the important functions related to normal physiology or/and pathology in this organ. The HLP spans 6 orders of magnitude in relative protein abundance and 78% of the proteins fall in the middle of this range. Of newly identified liver proteins, 82.5% are of low abundance. (4) Proteins involving in metabolism, transport, and coagulation and those containing active domains for metabolism, transport, and biosynthesis are significantly enriched in liver. (5) All 94 metabolic pathways in KEGG are touched to different extent. Of which, for 48 pathways, particularly those involved in metabolism of carbohydrates and amino acids, more than 80% of the component proteins have been detected. The liver-specific pathways, such as those participating in metabolism of bile acid and bilirubin and in biotransformation, are identified with remarkably high coverage. A total of 31 members of the cytochrome P450 family are identified, four of which have been observed for the first time in human liver. (6) Transport proteins involved in energy metabolism and secretion of both protein and bile acid are highly abundant. Three ion channels are described for the first time in liver. (7) The 800 proteins related to signal transduction and primarily involved in cellular recognition, localization, communication, and inflammation are present in the HLP data set. Insulin and adipocytokine pathways, which are involved in the regulation of glucose and fatty acids, are highly covered. (8) Transcription factors (309 in total) have been recognized at relatively low detection rates and abundance; however, transcription factors regulating gene expression related to transport, metabolism, and biosynthesis are detected at relatively higher coverage and the protein products of their target genes (100 in total), such as metabolic enzymes and plasma proteins, are also identified. (9) The overlap between the human liver and plasma proteomes is particularly noteworthy in the coagulation/anticoagulation/fibrinolysis and complement system. There is a significantly positive linear correlation between the abundance of coagulator proteins in liver and plasma.