HNF4a Mediated Formation of Hepatic Progentiors [array expression data set]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE104612 | GEO | 2019/01/28
REPOSITORIES: GEO
Similar Datasets
Project description:The pancreas and liver arise from a common pool of progenitors in the foregut endoderm; however, the underlying molecular mechanisms driving this lineage diversification are not fully understood. We combined human pluripotent stem cell guided differentiation and sequential CRISPR-Cas9 loss-of-function screening to uncover regulators of pancreatic specification. Here we report the discovery of a cell-intrinsic requirement for HHEX, a transcription factor (TF) associated with diabetes susceptibility. HHEX promotes pancreatic differentiation through cooperation with pancreatic TFs as well as common TFs like FOXA2 that are shared by both pancreas and liver differentiation programs. Furthermore, HHEX restricts differentiation plasticity, and deletion of HHEX shifts FOXA2 interaction towards cooperation with HNF4A, driving liver differentiation. Therefore, HHEX safeguards pancreatic differentiation by promoting lineage specification while simultaneously restricting cell fate plasticity, demonstrating how organ domain demarcation requires fine tuning of TF cooperation.
2022-04-29 | GSE181412 | GEO
Project description:The pancreas and liver arise from a common pool of progenitors in the foregut endoderm; however, the underlying molecular mechanisms driving this lineage diversification are not fully understood. We combined human pluripotent stem cell guided differentiation and sequential CRISPR-Cas9 loss-of-function screening to uncover regulators of pancreatic specification. Here we report the discovery of a cell-intrinsic requirement for HHEX, a transcription factor (TF) associated with diabetes susceptibility. HHEX promotes pancreatic differentiation through cooperation with pancreatic TFs as well as common TFs like FOXA2 that are shared by both pancreas and liver differentiation programs. Furthermore, HHEX restricts differentiation plasticity, and deletion of HHEX shifts FOXA2 interaction towards cooperation with HNF4A, driving liver differentiation. Therefore, HHEX safeguards pancreatic differentiation by promoting lineage specification while simultaneously restricting cell fate plasticity, demonstrating how organ domain demarcation requires fine tuning of TF cooperation.
2022-04-29 | GSE181478 | GEO
Project description:The pancreas and liver arise from a common pool of progenitors in the foregut endoderm; however, the underlying molecular mechanisms driving this lineage diversification are not fully understood. We combined human pluripotent stem cell guided differentiation and sequential CRISPR-Cas9 loss-of-function screening to uncover regulators of pancreatic specification. Here we report the discovery an unexpected, cell-intrinsic requirement for HHEX, a transcription factor (TF) associated with diabetes susceptibility. HHEX promotes pancreatic differentiation through cooperation with pancreatic TFs as well as common TFs like FOXA2 that are shared by both pancreas and liver differentiation programs. Furthermore, HHEX restricts differentiation plasticity, and deletion of HHEX causes a shift of FOXA2 interaction towards cooperation with HNF4A to drive liver differentiation. Our findings demonstrate a critical role for the fine tuning of TF cooperation in organ domain demarcation, as exemplified by how HHEX safeguards pancreatic differentiation by simultaneously promoting lineage specification and restricting cell fate plasticity.
2022-04-29 | GSE180521 | GEO
Project description:HNF4a and FOXA2 are two liver enriched transcription factors that have been shown capable of reprogramming fibroblasts into hepatocyte-like cells. However to date it is not yet understood how these master regulators, expressed in both embryonic and adult liver contribute to the transcriptional changes necessary for hepatocyte maturation during development. Consequently we undertook to identify binding sites and target genes for HNF4a and FOXA2 in the embryonic liver. A comparison of embryonic and adult liver TF binding patterns revealed widespread differentiation-dependent genome occupancy associated with changes in target gene expression during liver development.
2014-08-31 | GSE54520 | GEO
Project description:During mammalian development, liver differentiation is driven by signals which converge on multiple transcription factor networks. The hepatocyte nuclear factor signalling network is known to be essential for hepatocyte specification and maintenance. In these studies we demonstrate that nuclear HNF4a is essential for hepatic progenitor specification and the introduction of point mutations in HNF4a’s SUMO consensus motif leads to disrupted hepatocyte specification and maturation.
2019-10-31 | E-MTAB-7951 | biostudies-arrayexpress
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.
2021-09-01 | GSE165277 | GEO
Project description:HNF4a Mediated Formation of Hepatic Progentiors [array expression data set]
| PRJNA413300 | ENA
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 have been shown to be highly dependent on context. Here, we performed GR ChIP-seq in mouse liver to demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining tissue-specificity of GR action. In normal 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. Lost sites are characterised by HNF4 motifs and weak GRE motifs. Gained sites are characterised by strong GRE motifs, and 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.
2021-04-09 | E-MTAB-10224 | biostudies-arrayexpress
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 have been shown to be highly dependent on context. Here, we demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining tissue-specificity of GR action. In normal 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. Lost sites are characterised by HNF4 motifs and weak GRE motifs. Gained sites are characterised by strong GRE motifs, and typically show GR recruitment in non-liver tissues. These RNA-seq data demonstrate the functional importance of these HNF4A-regulated GR sites by showing evidence of an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver. In Hnf6-null liver, a far more minor effect on the glucocorticoid response is observed.
2021-04-09 | E-MTAB-10247 | biostudies-arrayexpress
Project description:To study the role of hepatic nuclear factor _ alpha (HNF4a_ in hepatogenesis, we used loxP-Cre technology to eliminate it from developing mouse livers. A comparison of control and experimental livers revealed that hepatocytes lacking HNF4a_failed to fully differentiate. Specifically, HNF4a null liver cells failed to express genes that are markers of mature hepatocytes including Gys2, Pck1, and G6pc. These cells also failed to form normal cellular junctions, which are critical for establishment of the hepatic epithelium [Parviz et al. (2003) Nat.Genet. 34, 292-96]. Because HNF4a functions as a transcription factor, we hypothesized that it regulates liver development by controlling the expression of genes whose products are essential in executing cellular differentiation and morphogenesis. To identify these genes, we compared expression profiles between HNF4a null and wild type E18.5 fetal livers using Affymetrix gene arrays. We identified 564 genes whose expression was decreased by at least 2.5-fold and 34 genes whose expression was increased by at least 2.5-fold when HNF4a was eliminated from hepatocytes. These represent genes involved in diverse molecular pathways, reflecting the pleiotropic phenotype of HNF4a null livers. Our goal was to use the information from the gene arrays to define the mechanisms through which HNF4a controls the generation of the hepatic epithelium. We identified 27 genes from our list of downregulated genes with either defined or predicted roles in cellular junctions and/or adhesion. Most striking was that loss of HNF4a altered the expression of genes encoding proteins involved in virtually all types of cellular junctions including tight junctions (Cldn1, Cldn-2, Cldn-12, Ocln, F11r/Jam1, Cxadr, Crb3), adherens junctions (Cdh1), desmosomes (Dsc2, Pkp2, Krt2-8), and gap junctions (Gjb1, Gjb2). Using immunoblotting and immunohistochemistry, we found that the expression of proteins representing each of these junction types was reduced or absent. Analysis of these genes for the presence of putative HNF4a binding sites revealed that 25 of 27 contain such sites. We have used chromatin immunoprecipitation to confirm that HNF4a occupies several of these sites in vivo, including Cdh1, Cldn1, and F11r/Jam1. From these data, we conclude that HNF4_ is a central mediator of the fully differentiated hepatocyte gene expression program and that it orchestrates the expression of cell junction and adhesion proteins required for establishing the hepatic epithelium. Experiment Overall Design: comparison of three hnf4 null livers to three control.
2007-12-01 | E-GEOD-3126 | biostudies-arrayexpress