Liver gene expression in animals with hepatocyte-specific deletion of JAK2
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE26188 | GEO | 2011/05/01
SECONDARY ACCESSION(S): PRJNA135013
REPOSITORIES: GEO
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Project description:Growth hormone signaling in hepatocytes is fundamentally important. Disruptions in this pathway have led to fatty liver and other metabolic abnormalities. Growth hormone signals through the JAK2/STAT5 pathway. Mice with hepatocyte specific deletion of STAT5 were previously shown to develop fatty liver. Our aim in this study was to determine the effect of deleting JAK2 in hepatocytes on liver gene expression. To do so, we generated animals with hepatocyte specific deletion of JAK2. Hepatocyte-specific JAK2-deficient mice (JAK2L) were generated by mating floxed JAK2 mice (in a mixed (C57Bl/6:129Sv) background) to mice carrying an Alb promoter-regulated Cre transgene on a 100% C57Bl/6 background purchased from the Jackson Labs. Livers were harvested from 8 week old animals for RNA extraction and hybridization.
2011-04-30 | E-GEOD-26188 | biostudies-arrayexpress
Project description:Impairment of hepatic growth hormone (GH)- janus kinase (JAK) 2- signal transducer and activator of transcription (STAT) 5 signaling is associated with non-alcoholic fatty liver disease, while persistently high levels of GH can result in hepatic inflammation and liver cancer. Despite its anti-steatotic functions, STAT5 in hepatocytes has been implicated to be a tumor suppressor, whose loss strongly accelerates tumor formation in the presence of high GH levels. Yet, it remains unclear whether the upstream kinase JAK2 exerts similar tumor-suppressive functions. To address this question, we crossed a mouse model of inflammatory liver cancer (GHtg) to mice harboring the hepatocyte-specific deletion of JAK2 (JAK2Îhep) and compared them to GHtgSTAT5Îhep mice. We show that JAK2 deficiency in the GHtg background resulted in profound steatosis at young age due to ectopic lipid redistribution and increased hepatic de novo lipogenesis. Generation of reactive oxygen species (ROS) was increased in all genotypes compared to wildtype controls, while DNA damage and lipid peroxidation were observed only in GHtg and GHtgSTAT5Îhep animals. Importantly, Affymetrix analysis revealed that the expression of glutathione S-transferases (GSTs), a major group of detoxification enzymes, was strongly upregulated in JAK2 deficient livers. In vitro and in vivo studies further confirmed that ruxolitinib-mediated inhibition of JAK2 led to significant upregulation of GSTs, indicating a direct involvement of JAK2 in the negative regulation of these genes. Strikingly, despite equally profound hepatosteatosis and ROS production as in GHtgSTAT5Îhep mice, loss of JAK2 significantly delayed tumor formation in GHtg mice. Conclusion: Thus, in absence of hepatic JAK2, mice were protected against elevated ROS-induced DNA damage and lipid peroxidation through significant expression of GSTs.
2016-10-01 | E-MTAB-3774 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver disease (NAFLD) has become a growing public health problem. However, the complicated pathogenesis of NAFLD contributes to the deficiency of effective clinical treatment. Here, we elucidated that liver-specific loss of Arid2 induced hepatic steatosis and this progression could be exacerbated by HFD. Mechanistic study revealed that ARID2 repressed JAK2-STAT5-PPARγ signaling pathway by promoting the ubiquitination of JAK2, which was mediated by NEDD4L, a novel E3 ligase for JAK2. ChIP assay revealed that ARID2 recruited CARM1 to increase H3R17me2 level at NEDD4L promoter and activated the transcription of NEDD4L. Moreover, inhibition of Jak2 by Fedratinib in liver-specific Arid2 knockout mice alleviated HFD-induced hepatic steatosis. Downregulation of ARID2 and the reverse correlation between ARID2 and JAK2 were also observed in clinical samples. Therefore, our study has revealed an important role of ARID2 in the development of NAFLD and provides a potential therapeutic strategy for NAFLD.
2022-11-17 | GSE216171 | GEO
Project description:Nonalcoholic fatty liver disease (NAFLD) ranges from steatosis to nonalcoholic steatohepatitis (NASH), that often progresses to hepatocellular carcinoma (HCC) through a largely undefined mechanism. NASH and HCC both depend on inflammatory signaling whose master regulator is the NFκB transcription factor family, activated by canonical and non-canonical pathways. Here, we investigated non-canonical NFκB-inducing kinase (NIK/MAP3K14) in metabolic NASH, NASH to HCC transition as well as in DEN-induced HCC. We revealed that hepatocyte-specific NIK deficiency (NIKLKO) ameliorated metabolic NASH complications and reduced hepatocarcinogenesis however, independent of its role in NFB pathway. Instead, hepatic NIK attenuated hepatoprotective JAK2/STAT5 signaling that is a prerequisite for NASH and NASH to HCC progression in mice and humans. Our data suggest NIK-mediated inhibitory JAK2 phosphorylation at serine 633 that might be amenable for future therapeutic interventions in patients.
2022-12-08 | GSE146049 | GEO
Project description:Non-alcoholic fatty liver disease is continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. Here, we integrated transcriptomic and chromatin accessibility analyses from human liver and mouse hepatocytes to identify lipotoxicity-sensitive transcription factors. We found that the transcription factors MAFK and TCF4 were activated in liver from NASH patients and by mouse hepatocyte lipotoxicity. Genetic deletion of these transcription factors protected hepatocytes against saturated fatty acid oversupply. Notably, MAFK- and TCF4-regulated gene expression linked to lipotoxicity closely correlated with transcriptional patters in fibrosis progression in NASH patients. Collectively, our findings uncovered novel molecular insights into lipotoxicityinduced NASH, revealing the relevance and therapeutic potential of MAFK and TCF4 in human disease.
2022-07-08 | PXD026717 | Pride
Project description:Notch signaling regulates cell-fate decisions in several developmental processes and cell functions. However, a role for Notch in hepatic thrombopoietin (TPO) production remains unclear. We noted thrombocytopenia in mice with hepatic Notch1 deficiency, and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control mice and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO mRNA levels, concomitant with lower numbers of platelets and impaired megakaryocyte differentiation and maturation, which were rescued by addition of exogenous TPO. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes, consistent with the RNA-seq analysis. JAK2/STAT3 phosphorylation and TPO production was also impaired in cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Consistently, hepatocyte-specific Notch1 deletion inhibited JAK2/STAT3 phosphorylation and hepatic TPO production induced by administration of desialylated platelets in vivo. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation in hepatocytes. Hepatocyte Ashwell-Morell receptor (AMR) (asialoglycoprotein receptor 1, ASGR1) physically associates with Notch1 and inhibition of AMR impaired Notch1 signaling activation and hepatic TPO production. Furthermore, blockage of Dll4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level.
2024-04-12 | GSE250529 | GEO
Project description:SPAG9-JAK2 is a novel fusion gene identified in a pediatric patient with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). In this study, we performed functional analysis of the SPAG9-JAK2 fusion to establish molecular targeted therapy. Ba/F3 cells expressing SPAG9-JAK2 generated by retroviral transduction (Ba/F3-SPAG9-JAK2), proliferated in the absence of IL-3, and exhibited constitutive phosphorylation of the tyrosine residues in the JAK2 kinase domain of the fusion protein and STAT3/STAT5. Mutation of tyrosine residues in the JAK2 kinase domain (SPAG9-JAK2 mut) abolished IL-3 independence, but had no influence on STAT3/STAT5 phosphorylation levels. Gene expression analysis revealed that Stat1 was significantly up-regulated in Ba/F3-SPAG9-JAK2 cells. STAT1 was also phosphorylated in Ba/F3-SPAG9-JAK2 but not SPAG9-JAK2 mut cells, suggesting that STAT1 is key for SPAG9-JAK2-mediated cell proliferation. Consistently, STAT1 induced expression of the anti-apoptotic proteins, BCL-2 and MCL-1, as did SPAG9-JAK2, but not SPAG9-JAK2 mut. Ruxolitinib abrogated Ba/F3-SPAG9-JAK2-mediated proliferation in vitro, but was insufficient in vivo. Venetoclax (a BCL-2 inhibitor) or AZD5991 (an MCL-1 inhibitor) enhanced the effects of ruxolitinib on Ba/F3-SPAG9-JAK2 in vitro. These findings suggest that activation of the JAK2-STAT1-BCL-2/MCL-1 axis contributes to SPAG9-JAK2-related aberrant growth promotion. BCL-2 or MCL-1 inhibition is a potential therapeutic option for B-ALL with SPAG9-JAK2 fusion.
2021-05-18 | GSE174578 | GEO
Project description:Cellular signal transduction is governed by multiple feedback mechanisms to elicit robust cellular decisions. We combined mathematical modeling and extensive time-resolved data sets in primary erythroid progenitor cells and dissected the roles of the two transcriptional feedback regulators of the SOCS family, CIS and SOCS3 in JAK2/STAT5 signaling. Our model revealed that both feedbacks are most effective at different ligand concentration ranges. To identify the relevant transcriptional feedback regulators that are involved in attenuation of Epo-induced JAK2-STAT5 signaling in addition to CIS, we performed a time-resolved genome-wide expression profiling of murine erythroid progenitor cells at the colony forming unit erythroid (CFU-E) stage up to 24 and 7 hours after EPO stimulation and in control, repectively. The analysis identified SOCS3 as the only further de novo regulated gene upon Epo-induced JAK2-STAT5 signaling. From subsequent mathematical modeling, we calculated the STAT5 response in previously unobserved Epo concentrations, which provided a quantitative link between cell survival and the integrated response of STAT5 in the nucleus. In conclusion, our combined modeling approach revealed novel insights into the orchestrated action of feedback control to regulate STAT5-mediated survival decisions over a broad range of ligand concentrations. Freshly sorted CFU-E cells were starved for 1 h in Panserin 401 supplemented with BSA and 50 µM β-Mercaptoethanol. Subsequently, cells were stimulated with 0.5 U/ml Epo or left untreated and RNA was extracted at different time points (0,1,2,3,4,5,6,7,8,14,19,24 hrs after Epo stimulation and at 0,1,2,3,4,5,6,7 hrs without Epo treatment) using the RNeasy Mini Plus Kit (Qiagen, Hilden, Germany).
2011-06-30 | E-GEOD-26151 | biostudies-arrayexpress
Project description:While PAX5 is an important tumor suppressor in B-ALL, it is also involved in oncogenic translocations coding for PAX5 fusion proteins. PAX5-JAK2 encodes a protein consisting of the PAX5 DNA-binding region fused to the constitutively active JAK2 kinase domain. Here, we studied the oncogenic function of PAX5-JAK2 in a mouse model expressing it from the endogenous Pax5 locus. The Pax5Jak2/+ mice rapidly developed an aggressive B-ALL in the absence of another cooperating mutation. The DNA-binding function and kinase activity of Pax5-Jak2, as well as IL-7 signaling, all contributed to leukemia development. Interestingly, all Pax5Jak2/+ tumors lost the wild-type Pax5 allele, allowing efficient DNA binding of Pax5-Jak2. While we could not find evidence for a nuclear role of Pax5-Jak2 as an epigenetic regulator, active phosphorylated Stat5 was present at a high level in Pax5Jak2/+ B-ALL tumors, consistent with increased expression of Stat5 target genes. Together, these data identified Pax5-Jak2 as an important nuclear driver of leukemia formation by maintaining phosphorylated Stat5 levels in the nucleus.
2022-02-04 | GSE174775 | GEO
Project description:Cellular signal transduction is governed by multiple feedback mechanisms to elicit robust cellular decisions. We combined mathematical modeling and extensive time-resolved data sets in primary erythroid progenitor cells and dissected the roles of the two transcriptional feedback regulators of the SOCS family, CIS and SOCS3 in JAK2/STAT5 signaling. Our model revealed that both feedbacks are most effective at different ligand concentration ranges. To identify the relevant transcriptional feedback regulators that are involved in attenuation of Epo-induced JAK2-STAT5 signaling in addition to CIS, we performed a time-resolved genome-wide expression profiling of murine erythroid progenitor cells at the colony forming unit erythroid (CFU-E) stage up to 24 and 7 hours after EPO stimulation and in control, repectively. The analysis identified SOCS3 as the only further de novo regulated gene upon Epo-induced JAK2-STAT5 signaling. From subsequent mathematical modeling, we calculated the STAT5 response in previously unobserved Epo concentrations, which provided a quantitative link between cell survival and the integrated response of STAT5 in the nucleus. In conclusion, our combined modeling approach revealed novel insights into the orchestrated action of feedback control to regulate STAT5-mediated survival decisions over a broad range of ligand concentrations.
2011-06-30 | GSE26151 | GEO