Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes
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ABSTRACT:
PROVIDER: PRJNA987704 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25030400_1.fastq.gz | Fastqsanger.gz | |||
| SRR25030400_2.fastq.gz | Fastqsanger.gz | |||
| SRR25030401_1.fastq.gz | Fastqsanger.gz | |||
| SRR25030401_2.fastq.gz | Fastqsanger.gz | |||
| SRR25030402_1.fastq.gz | Fastqsanger.gz |
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Project description:In all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet ER stress in the liver is uniquely accompanied by the suppression of metabolic genes, the coordination and purpose of which is largely unknown. Here, we combined in silico machine learning, in vivo liver-specific deletion of the master regulator of hepatocyte differentiation HNF4α, and in vitro manipulation of hepatocyte differentiation state to determine how the UPR regulates hepatocyte identity, and toward what end. Machine learning identified a cluster of correlated genes that were profoundly suppressed by persistent ER stress in the liver. These genes, which encode diverse functions including metabolism, coagulation, drug detoxification, and bile synthesis, are likely targets of the master regulator of hepatocyte differentiation HNF4α. The response of these genes to ER stress was phenocopied by liver-specific deletion of HNF4α. Strikingly, while deletion of HNF4α exacerbated liver injury in response to an ER stress challenge, it also diminished UPR activation and partially preserved ER ultrastructure, suggesting attenuated ER stress. Conversely, pharmacological maintenance of hepatocyte identity in vitro enhanced sensitivity to stress. Together, our findings suggest that the UPR regulates hepatocyte identity through HNF4α to protect ER homeostasis even at the expense of liver function.
2023-07-04 | GSE235849 | GEO
Project description:To define changes in gene expression resulting from loss of hnf4 in the small intestine. Keywords: genetic modification
2005-12-31 | GSE3124 | GEO
Project description:Upon infection of a mammalian host, Plasmodium parasites first replicate inside hepato-cytes, generating thousands of new parasites. Although Plasmodium intra-hepatic devel-opment represents a substantial metabolic challenge to the host hepatocyte, how infected cells respond to and integrate this stress remains poorly understood. Here, we present proteomic and transcriptomic analysis revealing that the endoplasmic reticulum (ER)-resident unfolded protein response (UPR) is activated in host hepatocytes upon Plasmo-dium berghei infection. The expression of XBP1s -the active form of the UPR mediator XBP1- and the liver-specific UPR mediator CREBH is induced by P. berghei infection in vivo. Furthermore, this UPR induction increases parasite liver burden. Altogether, our data suggests that ER stress is a central feature of P. berghei intra-hepatic development, contributing to the success of infection.
2016-04-20 | PXD002269 | Pride
Project description:Background and Aims: HNF4? is a nuclear hormone receptor transcription factor that has been shown to be required for hepatocyte differentiation and development of the liver. It has also been implicated in regulating expression of genes that act in the epithelium of the lower gastrointestinal tract. This implied that HNF4? might be required for development of the gut. Methods: We generated mouse embryos in which Hnf4? was ablated in the epithelial cells of the fetal colon using Cre-loxP technology. Embryos were examined using a combination of histology, immunohistochemistry, gene array and RT-PCR, and chromatin immunoprecipitation analyses to define the consequence of loss of HNF4? on colon development. Results: Embryos could be generated until E18.5 that lacked HNF4? in their colon. Although, early stages of colonic development occurred, HNF4? null colons failed to form normal crypts. In addition, goblet cell maturation was perturbed and expression of an array of genes that encode proteins with diverse roles in colon function was disrupted. Several genes whose expression in the colon was dependent on HNF4? contained HNF4?âbinding sites sequences within putative transcriptional regulatory regions and a subset of these sites were occupied by HNF4? in vivo. Conclusion: HNF4? is a transcription factor that is essential for development of the mammalian colon, regulates goblet cell maturation and is required for expression of genes that control normal colon function and epithelial cell differentiation. Experiment Overall Design: COMPARISON OF 3 MUTANT TO 2 CONTROL COLONS.
2008-06-12 | E-GEOD-3116 | biostudies-arrayexpress
Project description:HNF4 paralogs are redundantly required for proper villus elongation, differentiation and maturation in the developing gut. We find 5,391 chromatin regions become inaccessible upon HNF4 loss, and HNF4 binding sequences are most enriched in these regions. Genes nearby these 5,391 HNF4 dependent regions are associated with villus differentiation/maturation.
2019-07-29 | GSE128674 | GEO
Project description:To define changes in gene expression resulting from loss of hnf4 in the small intestine. Experiment Overall Design: hnf4 null intestines were generated by breeding hnf4loxp mice to vill-cre mice. Animals appeared to be healthy. Gene arrays were performed on two null and two control intestines.
2008-06-12 | E-GEOD-3124 | biostudies-arrayexpress
Project description:Through scRNA-sequencing of primary human hepatocytes (PHHs), we have identified four subgroups of hepatocytes. A phenotyping 5-probe cocktail (Sanofi-Aventis) has been used to assess their metabolic capacity. Upon cocktail treatment, the characterized four hepatocyte subgroups displayed differential gene expression profiles and exhibited xenobiotic metabolism-related specialization. Intracellular lipid accumulation achieved through loading the cells with free fatty acids (FFA, 2:1 oleic:palmitic acid), differently affected the four subgroups. Moreover, we have shown that intracellular fat accumulation diminishes the drug-related metabolic capacity of hepatocytes.
2023-09-19 | E-MTAB-11530 | biostudies-arrayexpress
Project description:We show that dHNF4 null mutant larvae are sensitive to starvation. Starved mutant larvae consume glycogen normally, but retain lipids in their midgut and fat body, and have increased levels of long chain fatty acids, suggesting that they are unable to efficiently mobilize stored fat for energy. HNF4 dependent transcripts were identified under fed and starved conditions. Microarray studies indicate reduced expression of genes that control lipid catabolism and beta-oxidation. Late second instar control and HNF4 mutant larvae were collected and fed or starved for 24 hours, and then RNA was isolated for analysis. Taken together, our results support a feed-forward model for dHNF4, in which fatty acids released from triglycerides activate the receptor, inducing enzymes that drive fatty acid oxidation for energy production. Keywords: expression profiling, HNF4, mutants, Affymetrix, Drosophila 2.0, starvation, TAG, fatty acid, beta-oxidation
2009-01-24 | GSE14531 | GEO
Project description:Drug-induced liver injury (DILI) is an important clinical problem. Here we used a genomics approach to establish the critical drug-induced toxicity pathways that act in synergy with the pro-inflammatory cytokine tumor necrosis factor M-oM-^AM-! (TNFM-oM-^AM-!) to cause cell death of liver HepG2 cells. Transcriptomics of the cell injury stress response pathways initiated by two hepatoxicants, diclofenac and carbamazepine, revealed the endoplasmic reticulum (ER) stress/translational initiation signaling and Nrf2 antioxidant signaling as two major affected pathways, which was similar to that observed for the majority of ~80 DILI compounds in primary human hepatocytes. The ER stress was primarily related to PERK and ATF4 activation and subsequent expression of CHOP, which was all independent of TNFM-NM-1 signaling. Identical ATF4 dependent transcriptional programs were observed in primary human hepatocytes as well as primary precision cut human liver slices. Targeted RNA interference studies revealed that while ER stress signaling through IRE1M-NM-1 and ATF6 acted cytoprotective, activation of the ER stress protein kinase PERK and subsequent expression of CHOP was pivotal for the onset of drug/TNF-induced apoptosis. While inhibition of the Nrf2-dependent adaptive oxidative stress response enhanced the drug/TNF cytotoxicity, Nrf2 signaling did not affect CHOP expression. Both hepatotoxic drugs enhanced expression of the translational initiation factor EIF4A1, which was essential for CHOP expression and drug/TNFM-oM-^AM-!-mediated cell killing. Our data support a model in which enhanced drug-induced translation initiates PERK-mediated CHOP signaling in an EIF4A1 dependent manner, thereby sensitizing towards caspase-8-dependent TNF induced apoptosis. 4 biological replicates of Diclofenac and 6 biological replicates of vehicle. 46 hours after isolation, cells were exposed to either 300 M-BM-5M DCF or the solvent DMSO for 24 hours.
2014-01-22 | E-GEOD-54256 | biostudies-arrayexpress
Project description:Dual β-catenin and γ-catenin loss in hepatocytes impacts their polarity through altered TGFβ and HNF4⍺ signaling
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