HNF4α nuclear localization correlates with the clinical progression of terminal hepatic failure in humans
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ABSTRACT:
PROVIDER: PRJNA555103 | ENA |
REPOSITORIES: ENA
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Project description:HNF4α is a transcription factor that plays a critical role in terminal hepatocyte failure. HNF4α-based reprogramming therapy can correct terminal liver failure in rats and humans. As liver disease progresses, HNF4α expression decreases in the nuclei of hepatocytes, leading to impaired regulation and hepatic function. Post-translational modifications (PTMs) are a fundamental regulatory mechanism of protein function and localization. In this study, we analyzed HNF4α localization and pathways involved in HNF4α PTMs in human hepatocytes at different stages of decompensated liver function upon Child-Pugh classification. RNA-seq analysis revealed that HNF4α and the PTMs-pathway related to AKT are down-regulation in cirrhotic hepatocytes with terminal failure. These findings were confirmed by protein expression, where the HNF4α nuclear levels are significantly reduced in Child‐Pugh B and C hepatocytes, whereas cytoplasmic expression of HNF4α was increased. Moreover, cMET and phospho-AKT were significantly reduced in Child‐Pugh B and C hepatocytes. The association and statistical contribution of cMET and phospho-AKT to the nuclear localization of HNF4α were confirmed by Spearman’s rank correlation test and pathway analysis. Principal component analysis was used to characterize the protein profiles related to the degree of liver dysfunction. Additionally, HNF4α acetylation was significantly reduced in failing human hepatocytes when compared to normal controls, demonstrating a significant correlation to the degree of hepatic function. Conclusion: These results suggest that the alterations in the cMET-AKT pathway directly correlate to HNF4α localization and the level of hepatic dysfunction. In conclusion, this study has therapeutic implications and suggests that manipulation of these pathways may restore hepatocyte function in terminal liver failure.
2020-03-19 | GSE134422 | GEO
Project description: Not available
| S-EPMC7262291 | biostudies-literature
Project description:Hepatocyte Nuclear Factor 4α (HNF4α), master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4α but not P2-HNF4α is expressed in normal adult liver while both P1- and P2-HNF4α are expressed in fetal liver and liver cancer. To determine the physiological function of the HNF4α isoforms, we compared P2-HNF4α-expressing exon swap mice to wildtype (WT) using RNA-seq, ChIP-seq, proteomics, protein binding microarrays (PBMs) and metabolomics. P2-HNF4α orchestrates a distinct transcriptomic and metabolomic profile.
2018-08-31 | GSE117972 | GEO
Project description:Hepatocyte Nuclear Factor 4α (HNF4α), master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4α but not P2-HNF4α is expressed in normal adult liver in fed conditions. Both P1- and P2-HNF4α are expressed in fetal liver. P2-HNF4α expression is increased in fasted conditions, high fat diet, alcoholic liver and liver cancer. To determine the target genes of the P1- and P2-HNF4α isoforms, we compared P2-HNF4α-expressing exon swap mice (a7HMZ) to wildtype (WT) male mice. Liver ChIP-seq samples were taken at 10:30 AM (ZT 3.5)
2023-05-10 | GSE231538 | GEO
Project description:HNF4α is a nuclear receptor regulating the transcription of genes involved mainly in development, cell differentiation and metabolism. Opposite functions for the two classes of P1 and P2 isoforms of HNF4α have recently been highlighted. These classes include 12 variants of HNF4α that can be expressed by the use of two promoters and by alternative splicing. Until now, the characterization of this transcription factor has ignored this diversity and has remained confined to the study of a fraction of the isoforms. We therefore wanted to clarify the situation by specifically characterizing the transcriptional functions of the 12 isoforms of HNF4α. We have generated for this purpose stable lines expressing each isoform of HNF4α in HCT 116 cells. We analyzed the whole transcriptome associated with each isoform by sequencing RNA, as well as their proteome by a BioID approach coupled to quantitative mass spectrometry. We noted major differences in the transcriptional function of the 12 isoforms. The α4, α5 and α6 isoforms have been characterized for the first time, and show a greatly reduced transcriptional potential. We have shown that these isoforms are unable to recognize the consensus response element of HNF4α. The α1 and α2 isoforms are the most potent regulators of gene expression, while the α3 isoform exhibits significantly reduced activity. Several transcription factors and coregulators have been identified as potential specific partners for certain HFH4α isoforms. The IRF-2BP2 co-repressor interacts specifically with isoforms which include the long form of the F domain of HNF4α. This specific interaction could explain the large number of genes modulated negatively by α1 and α2 compared to α3. The analysis integrating the vast amount of transcriptomic and proteomic data allows the identification of transcriptional regulatory mechanisms specific to certain isoforms, demonstrating the importance of considering all isoforms which can have diverse functions.
2020-04-17 | PXD012146 | Pride
Project description:Background & Aims: The role of HNF4α has been extensively studied in hepatocytes and pancreatic β cells, but emerging evidence indicates that HNF4α is a key regulator of intestinal epithelial cell differentiation as well. The aim of the present work is to identify HNF4α target genes in the intestine in order to elucidate the role of HNF4α in differentiation of the intestinal epithelial cells. Results: One thousand one hundred and seventy-six genes were identified as HNF4α targets, many of which have not previously been described as being regulated by HNF4α. The 1,176 genes contributed significantly to gene ontology (GO) pathways categorized by lipid and amino acid transport and metabolism. A thorough analysis of Cdx-2, trehalase, and cingulin promoters verified that these genes are regulated by HNF4α. In each case we were able to identify a functional HNF4α binding site in their promoters. Conclusions: HNF4α regulation of the Cdx-2 promoter unravels a transcription factor network also including HNF1α and β, all of which are transcription factors involved in intestinal development and gene expression. Keywords: ChIP-CHIP and expression data
2007-05-10 | GSE7745 | GEO
Project description:Background Worldwide, gastric cancer is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. Objective To determine oncogenic mechanisms and novel therapeutic targets specific for gastric cancer by identifying commonly dys-regulated genes from the tumors of both Asian-Pacific and Caucasian patients. Design We generated transcriptomic profiles of 22 Caucasian gastric cancer tumors and their matched non-cancerous samples, and performed an integrative analysis across different gastric cancer gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signaling pathways by RNAi and/or pharmacologic inhibition. Results We found that HNF4α upregulation was a key signaling event in gastric tumors from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumor cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signaling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest, and tumor growth inhibition. HNF4α also regulated WNT signaling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumors. Conclusions Our results indicate that HNF4α is a targetable oncoprotein in gastric cancer, is regulated by AMPK signaling through AMPKα, and resides upstream of WNT signaling. HNF4α may regulate “metabolic switch” characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signaling cascade represents a potentially targetable pathway for drug development. Integrative analysis of Caucasian and Asian-Pacific gastric tumor expression datasets (including newly generated transcriptomic profiling of 22 tumors in this study) revealed a relatively small common sets of highly overexpressed genes.
2014-11-15 | E-GEOD-63288 | biostudies-arrayexpress
Project description:Rats overexpressing the human renin and angiotensinogen genes die after seven weeks of end organ damage. They develop hypertension, heart hypertrophy and proteinuria.We compared terminal heart failure, these are indeed terminally ill to double transgenic animals suffering on hypertension, proteinuria and heart hypertrophy. In addition, Losartan-treated animals (10 mg/kg/d)showed similar physiological parameters (normotension, no proteinuria and no heart hypertrophy compared to control sprague dawley rats. Keywords: other
2005-01-03 | GSE1557 | GEO
Project description:Polyglutamine(polyQ) expansion of ?1A voltage-dependent calcium channel (Cav2.1) is the causative mutation of spinocerebellar ataxia type 6 (SCA6). The C-terminal fragment (CTF) of Cav2.1 makes aggregates in the cytoplasm of SCA6 Purkinje cells and may relate to the pathogenesis. In order to identify genes associated with polyQ expansion and subcellular localization of CTF, we analyzed gene expression profiles of PC12 rat pheochromocytoma cells using Tet-off system. We exmined gene expression profiles of Tet-off PC12 cells using the following four recombinant C-terminal fragments (rCTFs): rCTF-Q13-NLS, rCTF-Q13-NES, rCTF-Q28-NLS and rCTF-Q28-NES. We obtained gene expression data of both Dox (+) and Dox (-) conditions for each CTF. All assays were performed in duplicate.
2013-03-13 | E-GEOD-26933 | biostudies-arrayexpress
Project description:Hepatocyte nuclear factor 4alpha (HNF4α) is a nuclear receptor with an emerging role in the gut. While HNF4α has been implicated in colitis and colon cancer in humans, deciphering its functional role is complicated by the existence of two promoters (P1 and P2) in theHNF4A gene that drive the expression of multiple isoforms in the adult intestine. In this study we investigate the roles of P1- and P2-driven HNF4α under conditions of homeostasis, colitis and colitis-associated colon cancer (CAC). P1- and P2-HNF4α are differentially expressed in the differentiated and proliferative compartments of the normal colonic crypt, respectively. Expression profiling of untreated exon swap mice suggests distinct functions of the isoforms that were corroborated in migration and ion transport assays.
2016-05-23 | GSE47731 | GEO