ChIP-Seq analysis of HNF4A and FOXA2 in embryonic mouse liver
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE54520 | GEO | 2014/08/31
SECONDARY ACCESSION(S): PRJNA236762
REPOSITORIES: GEO
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Project description:In each cell type the expression of genes is regulated by the action of a large number of transcription factors, but so far we have only a rudimentary knowledge of the location of the gene regulatory elements where they bind. This can now be addressed with genome-wide ChIP experiments. In a previous ChIP-chip study of USF1 and USF2 we found evidence also of binding of GABP, FOXA2 and HNF4a within the enriched regions. Here we have applied ChIP-seq for these transcription factors and identified 3064 peaks of enrichment for GABP, 7266 for FOXA2 and 18783 for HNF4a. HNF4a and FOXA2 binding was found in at least half of the regions previously identified as bound by USF2 but not USF1, showing that they frequently bind the same regulatory elements. GABP peaks were found at transcription start sites whereas 94 % of FOXA2 and 90 % of HNF4a peaks were located at other positions. We developed a method based on the high resolution achieved by ChIP-seq to accurately define TFBS within peaks, and found the predicted sites to have an elevated conservation level compared to peak centers; however the majority of bindings were not evolutionary conserved. An unexpected interaction between HNF4a and GABP was seen at TSS, with as many as 1/3 of the HNF4a positive promoters being bound also by GABP, and co-immunoprecipitations show that these factors are in the same complex in the nucleus.
2009-06-09 | E-MTAB-115 | biostudies-arrayexpress
Project description:In each cell type the expression of genes is regulated by the action of a large number of transcription factors, but so far we have only a rudimentary knowledge of the location of the gene regulatory elements where they bind. This can now be addressed with genome-wide ChIP experiments. In a previous ChIP-chip study of USF1 and USF2 we found evidence also of binding of GABP, FOXA2 and HNF4a within the enriched regions. Here we have applied ChIP-seq for these transcription factors and identified 3064 peaks of enrichment for GABP, 7266 for FOXA2 and 18783 for HNF4a. HNF4a and FOXA2 binding was found in at least half of the regions previously identified as bound by USF2 but not USF1, showing that they frequently bind the same regulatory elements. GABP peaks were found at transcription start sites whereas 94 % of FOXA2 and 90 % of HNF4a peaks were located at other positions. We developed a method based on the high resolution achieved by ChIP-seq to accurately define TFBS within peaks, and found the predicted sites to have an elevated conservation level compared to peak centers; however the majority of bindings were not evolutionary conserved. An unexpected interaction between HNF4a and GABP was seen at TSS, with as many as 1/3 of the HNF4a positive promoters being bound also by GABP, and co-immunoprecipitations show that these factors are in the same complex in the nucleus. ArrayExpress Release Date: 2009-06-10 Publication Title: Molecular interactions between HNF4a, FOXA2 and GABP identified at regulatory DNA elements through ChIP-sequencing Publication Author List: Ola Wallerman, Mehdi Motallebipour, Stefan Enroth, Kalicharan Patra, MadhuSudan Reddy Bysani, Jan Komorowski, Claes Wadelius Person Roles: submitter Person Last Name: Wallerman Person First Name: Ola Person Mid Initials: Person Email: ola.wallerman@genpat.uu.se Person Phone: Person Address: IGP, Rudbecklab Person Affiliation: Uppsala University
2011-02-05 | GSE25694 | GEO
Project description:HNF4a has been shown to be a central regulator of hepatocyte differentiation and function in adult mice. It was recently shown the HNF4a regulates the onset of hepatic gene expression during liver differentiation in vitro and is critical for the specification of liver towards a hepatic fate We examined the global gene expression of the differentiaiton of iPS cells into specified hepatic cells on consecutive days of liver differentiation (Mallanna et al 2013) to determine the onset of hepatic gene expression and the role HNF4a plays during hepatic specification.
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Project description:ChIP-seqs of BMAL1, HNF4A, FOXA2, H3K4me1, and H3K27ac were profiled in mouse liver tissues upon Hnf4a or Bmal1 knockout. BMAL1, H3K4me1, and H3K27ac ChIP-seq were profiled in U2OS cells ectopically expressing HNF4A.
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Project description:HNF4a is an important liver transcription factor that regulates at least a thousand genes in the liver. Here we used expression profiling in HepG2 cells, a hepatocellular carcinoma cell line, in which HNF4a was knocked down by RNAi to identify some of those target genes. This dataset accompanies the article in Hepatology 2010 Feb;51(2):642-53. Integrated approach for the identification of human hepatocyte nuclear factor 4alpha target genes using protein binding microarrays by Bolotin E, Liao H, Ta TC, Yang C, Hwang-Verslues W, Evans JR, Jiang T, Sladek FM.
2011-05-05 | GSE29084 | GEO
Project description:The mRNA-based therapeutics such as COVID-19 vaccines are rapidly progressing into the clinic with a tremendous potential of benefiting millions of people worldwide. Therapeutic targeting of injuries that require transient restoration of proteins by mRNA delivery is an attractive aspect, however until recently, it has remained poorly explored. In this study, we examined for the first time therapeutic utility of mRNA delivery in liver fibrosis and cirrhosis, which contributes to millions of deaths, annually. Here, demonstrated the therapeutic efficacy of the human transcription factor hepatic nuclear factor alpha (HNF4A) encoding mRNA in murine chronically injured liver leading to fibrosis and cirrhosis. We investigated restoration of hepatocyte functions by HNF4A mRNA transfection in vitro, and analyzed the attenuation of liver fibrosis and cirrhosis in multiple mouse models, by delivering hepatocyte-targeted biodegradable lipid nanoparticles (LNP) encapsulating HNF4A mRNA. To identify potential mechanism, we performed microarray-based gene expression profiling, single cell RNA sequencing, and chromatin immunoprecipitation. We used primary liver cells and human liver buds for further functional validation. Expression of HNF4A encoding mRNA led to restoration of metabolic activity of fibrotic primary murine and human hepatocytes in vitro. Repeated in vivo delivery of HNF4A mRNA encapsulated-LNP induced a robust inhibition of fibrogenesis in four independent mouse models of hepatotoxin- and cholestasis-induced liver fibrosis. Mechanistically, we discovered that paraoxonase 1 is a direct target of HNF4A and it contributes to HNF4A-mediated attenuation of liver fibrosis via modulation of liver macrophages and hepatic stellate cells. Collectively, our findings provide the first direct preclinical evidence of the applicability of HNF4A mRNA therapeutics for the treatment of fibrosis in the liver.
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Project description:The aim of this study was to test, in vivo, if Foxa2 inhibits HNF6-mediated transcription in the liver. We utilized hepatocyte-specific gene ablation of Foxa2 and the Mouse PromoterChip BCBC 3.0 and Mouse PancChip 5.0 cDNA microarrays to investigate HNF6 binding to its target promoters in vivo in the presence or absence of Foxa2. For the mouse promoter microarray analysis, chromatin immunoprecipitation using anti-HNF6 antibodies was performed on chromatin isolated from Foxa2loxP/loxP Alfp.Cre and control mouse livers. Along with sheared genomic DNA (common reference), the immunoprecipitated DNA was amplified, labeled and hybridized to the Mouse PromoterChip BCBC 3.0. For microarray analysis of gene expression, liver RNAs were isolated from three Foxa2loxP/loxP Alfp.Cre and three control mice. RNAs were reverse transcribed, labeled, and hybridized to the Mouse PancChip 5.0. Overall, our studies demonstrate that HNF6 binds to and regulates its target promoters in vivo in the presence and absence of Foxa2 and that the expression levels of HNF6 targets are not influenced by Foxa2.
2007-09-14 | E-CBIL-36 | biostudies-arrayexpress
Project description:HNF4a is an important liver transcription factor that regulates at least a thousand genes in the liver. Here we used expression profiling in HepG2 cells, a hepatocellular carcinoma cell line, in which HNF4a was knocked down by RNAi to identify some of those target genes. This dataset accompanies the article in Hepatology 2010 Feb;51(2):642-53. Integrated approach for the identification of human hepatocyte nuclear factor 4alpha target genes using protein binding microarrays by Bolotin E, Liao H, Ta TC, Yang C, Hwang-Verslues W, Evans JR, Jiang T, Sladek FM. RNA interference (RNAi) against HNF4a2 was performed in HepG2 cells using small, interfering RNAs (siRNAs) corresponding to nucleotides +179 to +197 of human HNF4A (NM_178849, sense siRNA: 5'-UGUGCAGGUGUUGACGAUGdTdT-3', antisense siRNA 5'-CAUCGUCAACACCUGCACAdTdT-3') (Dharmacon, Lafayette, CO). Total RNA was extracted with Trizol (Life Technologies, Carlsbad, CA) and reverse transcribed with the Reverse Transcription System (Promega, Madison, WI). Polymerase chain reaction (PCR) amplification was performed in the linear range (see Supporting Table 3B for a list of PCR primers). Expression profiling analysis was performed with Affymetrix oligonucleotide arrays (HGU133 Plus 2.0) using RNA from control (PGL3 siRNA) or treated (HNF4a siRNA) HepG2 cells
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Project description:The glucocorticoid receptor (GR) is a nuclear hormone receptor critical to the regulation of energy metabolism and the inflammatory response. The actions of GR are highly dependent on cell type and environmental context. Here, we demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver-specificity of GR action. In normal mouse liver, the HNF4 motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites found within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodelled, with both loss and gain of GR recruitment evident. Loss of chromatin accessibility at HNF4A-marked sites leads to loss of GR binding at weak GRE motifs. GR binding is gained at sites characterised by strong GRE motifs, which typically show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is further demonstrated by evidence of an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.
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