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Expression profile analysis of the inflammatory response regulated by hepatocyte nuclear factor 4?.

ABSTRACT: BACKGROUND: Hepatocyte nuclear factor 4? (HNF4?), a liver-specific transcription factor, plays a significant role in liver-specific functions. However, its functions are poorly understood in the regulation of the inflammatory response. In order to obtain a genomic view of HNF4? in this context, microarray analysis was used to probe the expression profile of an inflammatory response induced by cytokine stimulation in a model of HNF4? knock-down in HepG2 cells. RESULTS: The expression of over five thousand genes in HepG2 cells is significantly changed with the dramatic reduction of HNF4? concentration compared to the cells with native levels of HNF4?. Over two thirds (71%) of genes that exhibit differential expression in response to cytokine treatment also reveal differential expression in response to HNF4? knock-down. In addition, we found that a number of HNF4? target genes may be indirectly mediated by an ETS-domain transcription factor ELK1, a nuclear target of mitogen-activated protein kinase (MAPK). CONCLUSION: The results indicate that HNF4? has an extensive impact on the regulation of a large number of the liver-specific genes. HNF4? may play a role in regulating the cytokine-induced inflammatory response. This study presents a novel function for HNF4?, acting not only as a global player in many cellular processes, but also as one of the components of inflammatory response in the liver.

SUBMITTER: Wang Z

PROVIDER: S-EPMC3053261 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Expression profile analysis of the inflammatory response regulated by hepatocyte nuclear factor 4α.

Wang Zhongyan Z Bishop Eric P EP Burke Peter A PA

BMC genomics 20110225

<h4>Background</h4>Hepatocyte nuclear factor 4α (HNF4α), a liver-specific transcription factor, plays a significant role in liver-specific functions. However, its functions are poorly understood in the regulation of the inflammatory response. In order to obtain a genomic view of HNF4α in this context, microarray analysis was used to probe the expression profile of an inflammatory response induced by cytokine stimulation in a model of HNF4α knock-down in HepG2 cells.<h4>Results</h4>The expression ...[more]

PMID: 21352552

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Project description:AIM:To uncover the role of hepatocyte nuclear factor 4 alpha (HNF4?) in regulating hepatic expression of microRNAs. METHODS:Microarray and real-time PCR were used to determine hepatic expression of microRNAs in young-adult mice lacking Hnf4? expression in liver (Hnf4?-LivKO). Integrative genomics viewer software was used to analyze the public chromatin immunoprecipitation-sequencing datasets for DNA-binding of HNF4?, RNA polymerase-II, and histone modifications to loci of microRNAs in mouse liver and human hepatoma cells. Dual-luciferase reporter assay was conducted to determine effects of HNF4? on the promoters of mouse and human microRNAs as well as effects of microRNAs on the untranslated regions (3'UTR) of two genes in human hepatoma cells. RESULTS:Microarray data indicated that most microRNAs remained unaltered by Hnf4? deficiency in Hnf4?-LivKO mice. However, certain liver-predominant microRNAs were down-regulated similarly in young-adult male and female Hnf4?-LivKO mice. The down-regulation of miR-101, miR-192, miR-193a, miR-194, miR-215, miR-802, and miR-122 as well as induction of miR-34 and miR-29 in male Hnf4?-LivKO mice were confirmed by real-time PCR. Analysis of public chromatin immunoprecipitation-sequencing data indicates that HNF4? directly binds to the promoters of miR-101, miR-122, miR-194-2/miR-192 and miR-193, which is associated with histone marks of active transcription. Luciferase reporter assay showed that HNF4? markedly activated the promoters of mouse and human miR-101b/miR-101-2 and the miR-194/miR-192 cluster. Additionally, miR-192 and miR-194 significantly decreased activities of luciferase reporters for the 3'UTR of histone H3F3 and chromodomain helicase DNA binding protein 1 (CHD1), respectively, suggesting that miR-192 and miR-194 might be important in chromosome remodeling through directly targeting H3F3 and CHD1. CONCLUSION:HNF4? is essential for hepatic basal expression of a group of liver-enriched microRNAs, including miR-101, miR-192, miR-193a, miR-194 and miR-802, through which HNF4? may play a major role in the post-transcriptional regulation of gene expression and maintenance of the epigenome in liver.

Dataset Information

Expression profile analysis of the inflammatory response regulated by hepatocyte nuclear factor 4?.

Publications

Expression profile analysis of the inflammatory response regulated by hepatocyte nuclear factor 4α.

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