TRANSCRIPTIONAL REGULATION IN THE EARLY PHASE OF LIVER REGENERATION

VYTAUTAS MAGNUS UNIVERSITY Eglė Juškevičiūtė TRANSCRIPTIONAL REGULATION IN THE EARLY PHASE OF LIVER REGENERATION Doctoral dissertation Physical sciences, biochemistry (04 P) Kaunas, 2009 VYTAUTO DIDŽIOJO UNIVERSITETAS Eglė Juškevičiūtė TRANSKRIPCINIS ANKSTYVOJO KEPENŲ REGENERACIJOS TARPSNIO REGULIAVIMAS Daktaro disertacija Fiziniai mokslai, biochemija (04 P) Kaunas, 2009 The work described was carried out at Vytautas Magnus University and Thomas Jefferson University in 2002-2009 Research supervisor: Prof habil dr Vida Mildažienė (Vytautas Magnus University) Consultant: Prof dr Jan B Hoek (Thomas Jefferson University, Philadelphia) Table of contentS ABBREVIATIONS .7 INTRODUCTION .9 LITERATURE REVIEW 12 1.1 General features of liver regeneration .12 1.2 Cellular mechanisms of liver regeneration 14 1.3 The hepatocyte cell cycle 16 1.4 Hemodynamic changes after partial hepatectomy .17 1.5 Early phase of liver regeneration .19 1.5.1 Matrix remodeling after partial hepatectomy 21 1.5.2 Notch and Jagged protein 21 1.5.3 Activation of constitutively expressed transcription factors after PHx .22 1.5.4 Expression of immediate early growth response genes after PHx 23 1.6 Signaling mechanisms in liver regeneration .24 1.6.1 Cytokine signaling .25 1.6.2 The role of growth factors in liver regeneration 31 1.6.3 Growth factors with paracrine effects .33 1.6.4 The growth factor – cytokine interaction 34 1.6.5 Signaling through adenine nucleotides 36 1.6.6 Metabolic pathways and liver regeneration .37 1.7 Liver mass and regeneration capacity .37 1.8 Maintaining liver functions during regeneration .39 1.9 Proliferation and apoptosis in hepatocytes: reactive oxygen species 40 1.9.1 Concluding remarks 43 MATERIALS AND METHODS .44 2.1 Materials 44 2.2 Animal protocols .44 2.2.1 Animals and diet 44 2.2.2 Surgical procedure .44 2.3 RNA isolation 45 2.4 Microarray fabrication .45 2.5 Probe preparation 46 2.5.1 Vector RNA probe .46 2.5.2 Rat liver total RNA samples 49 2.6 Slide preparation and scanning 50 2.7 Data normalization 50 2.8 ANOVA response model 51 2.9 Cluster analysis 51 2.10 Quantitative reverse transcription polymerase chain reaction 52 2.11 Functional annotation 54 2.12 Transcriptional regulatory network analysis .54 2.13 Nuclear extract preparation .54 2.14 Protein quantification 55 2.15 Transcription factor activation assays .56 2.15.1 TransAM assay 56 2.15.2 TransFactor universal colorimetric assay 57 2.16 Chromatin immunoprecipitation assay 58 2.16.1 Chromatin crosslinking .58 2.16.2 Chromatin shearing 58 2.16.3 Immunoprecipitation reaction 59 2.16.4 DNA purification .59 2.16.5 Analysis of DNA fragments 60 RESULTS 61 3.1 Identification of temporally regulated genes during liver regeneration 61 3.2 Identification of co-regulated clusters of differentially expressed genes 71 3.3 Validation of microarray data with qRT-PCR 72 3.4 Interference with purine nucleotide signaling affects c-fos expression .73 3.5 Liver regeneration function-relevant gene expression 74 3.5.1 Transcription related genes 75 3.5.2 Signal transduction related genes 76 3.5.3 Cell proliferation and cell cycle related genes 78 3.5.4 3.6 Stress and inflammatory response related genes .79 Transcriptional Regulatory Network Analysis 80 3.6.1 Candidate TFs in the onset of liver regeneration 80 3.6.2 Activation of transcription factors .82 3.6.3 Binding of NF-κB to Sod2, Mt1a and Cebpb promoters 85 3.6.4 Functional gene categories regulated by transcription factors 86 DISCUSSION 90 CONCLUSIONS .93 SANTRAUKA 94 ACKNOWLEDGEMENT 96 REFERENCES 97 ABBREVIATIONS ANOVA analysis of variance AP activator protein ARL augmentor of liver regeneration aa-dUTP 5-(3-aminoallyl)-2’-deoxyuridine-5’-triphosphate ATP adenosine triphosphate ATF activating transcription factor BSA bovine serum albumine BRN brain-2 class III POU-domain protein BTG B-cell translocation gene C/EBP CCAAT-enhancer-binding protein CRE cAMP response element CREB cAMP response element binding CT cardiotrophin Ct cycle at threshold DMSO dimethylsulfoxide DNA deoxyribonucleic acid DUSP-6 dual specificity phosphoatase EGF epidermal growth factor ER endoplasmic reticulum ERK extracellular signal-regulated kinase FDR false discovery rate FGF fibroblast growth factor FMO flavin containing monooxygenase G6Pase glucose-6-phosphatase GO Gene Ontology HB-EGF heparin-binding epidermal growth factorlike growth factor HGF hepatocyte growth factor HNF-1 hepatic nuclear factor HRP horse radish peroxidase HSS hepatic stimulatory substance IGF insulin-like growth factor IGFBP insulin-like-growth-factor-binding protein IκB inhibitor of NF-κB IKK IκB kinase IL interleukin iNOS inducible nitric oxide synthase JAK Janus-kinase-family JNK Jun amino-terminal kinase KLF Kruppel-like factor KNG kininogen LEF-1 lymphoid enhancer factor L-NAME N-nitro-L-arginine methyl ester LPS lipopolysaccharide Lowess locally weighted scatterplot smoothing MAPK mitogen-activated protein kinase MIAME MKK MMP MT mTOR NF-κB OSM PAINT PAM PAX-6 PBEF PBL PCR PEPCK pERK PHx PI3K PP2A PVE PVP qPCR qRT-PCR RNA ROS RT SC SCF SIN-1 SOD SOCS STAT TAN TGF TF TNF TNFR TRNA tRNA TTP uPA VEGF vRNA ZFP minimal information about microarray experiment MAPK kinase matrix metalloproteinase metallothionein mammalian target of rapamycin nuclear factor for the kappa chain of B cells oncostatin M promoter analysis and interaction network generation tool partitioning around medoids paired box gene pre-B cell colony-enhancing factor portal vein branch ligation polimerase chain reaction phosphoenolpyruvate carboxykinase phosphorylated extracellular signal-regulated kinases partial hepatectomy phosphatidylinositol 3-kinase protein phosphatase 2A portal vein embolization portal vein pressure quantitative PCR quantitative reverse transcription PCR ribonucleic acid reactive oxygen species reverse transcription silhouette coefficient stem-cell factor 3-morpholinosydnonimine superoxide dismutase suppressor of cytokine signaling signal transducer and activator of transcription total adenine nucleotides transforming growth factor transcription factor tumor necrosis factor TNF receptor transcriptional regulatory network analysis transfer RNA tristetraprolin urokinase-type plasminogen activator vascular endothelial growth factor vector RNA zinc finger protein INTRODUCTION Actuality of the problem The onset and progression of liver regeneration following acute injury reflects a complex program of responses involving growth factors, cytokines, hormones, matrix components and other factors These extracellular mediators activate a carefully orchestrated sequence of intracellular signals resulting in a system-wide coordinated program of gene expression alterations and associated changes in the functional state of the liver cells (Fausto et al., 2006; Michalopoulos and DeFrances, 1997; Michalopoulos, 2007; Taub, 2004) Following the largely uncharacterized signals that mark the recognition of tissue damage after partial hepatectomy (PHx) and the onset of regeneration, which may include hemodynamic changes and stress signals mediated by adrenergic and purinergic agonists (Crumm et al., 2008), hepatocytes emerge from the quiescent (G 0) state to enter the pre-replicative phase of the cell cycle (G1) (Fausto, 2000; Fausto et al., 2006; Taub, 2004) The exit from quiescence (sometimes referred to as “priming”) is controlled by a wide range of signals from growth factors (HGF, TGF-α), cytokines, (tumor necrosis factor-α (TNF-α), interleukin-6) and structural components affected by proteases, such as urokinase plasminogen activator (uPA) and matrix metalloprotease-9 (MMP9) (Cressman et al., 1996; Fausto et al., 2006; Michalopoulos and DeFrances, 1997; Michalopoulos, 2007; Taub, 2004; Yamada et al., 1997) These and other signals result in the activation of a variety of transcription factors (TFs) important during the initial stages of liver regeneration before the onset of de novo protein synthesis and entry into the cell cycle (Taub, 2004) Specific TFs, such as nuclear factor-κB (NF-κB), signal transducer and activator of transcription (STAT-3), CCAAT enhancer-binding protein β (C/EBP-β), and activator protein (AP-1) are rapidly activated in the remnant liver within minutes to hours after PHx (Cressman et al., 1995; FitzGerald et al., 1995; Greenbaum et al., 1998; Heim et al., 1997) These events lead to the first phase of gene expression, referred to as the immediate early phase, which lasts for approximately hours in the rat The protooncogenes c-fos, c-jun and c-myc were among the first genes to be identified in this group (Morello et al., 1990; Thompson et al., 1986) Previous studies by Taub and colleagues identified a large set of genes participating in the immediate early response to PHx, which includes transcription factors, tyrosine phosphatases, as well as secreted and intracellular metabolic proteins (Haber et al., 1993; Taub, 1996) Characterizing changes in gene expression using microarray technology has provided new insight into the regulation of liver regeneration (Arai et al., 2003; Otu et al., 2007; Su et al., 2002; White et al., 2005) Notably, a broad range of cellular processes appears to be represented among up- or down-regulated genes Although the major emphasis in liver regeneration has been on signals that lead to cell proliferation, the response to PHx is much broader Liver cells display a highly dynamic and coordinated response profile that affects almost every aspect of cell functioning (Michalopoulos, 2007) However, our understanding of the temporal patterns of gene expression that occur during the course of liver regeneration and of the upstream regulatory signals responsible for these patterns is still limited Studies of liver regeneration have important clinical implications Experimental data from animal models provide vital information to enhance the safety using partial livers from living donors for transplantation, increasing the number of organs that are available for transplantation (Taub, 2004) Partial hepatectomy is also performed in humans, in order to resect solitary liver metastases or repair trauma (Michalopoulos, 2007) Understanding the regulatory mechanisms of liver regeneration helps better define the pathological conditions in which liver regeneration is impaired and will ultimately provide new treatment options for patients with liver damage Aim of this study: To get insight into the transcriptional network co-regulating gene expression in the early phase of liver regeneration Tasks of this study: To determine temporal gene expression profile in regenerating rat liver at 1-6 hours after 70% partial hepatectomy To test the effects of inhibitors of ATP release or purinergic receptor activation on the expression of immediate early genes in the regenerating liver To identify the candidate transcription factors involved in regulation of gene expression in the initial phase of liver regeneration To confirm 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These and other signals result in the activation of a variety of transcription factors (TFs) important during the initial stages of liver regeneration before the onset of de novo protein synthesis... supplies the left lateral and medial lobes of the liver This procedure forces all portal blood through the remaining 1/3 of the liver tissue as does removal of 2/3 of the liver in PHx PBL causes an increase... transcription factors involved in regulation of gene expression in the initial phase of liver regeneration To confirm activation of identified candidate transcription factors in regenerating rat liver Scientific