Transcriptomic analysis of hepatocyte-like cells generated by doxycycline inducible expression of HNF4A, HNF1A and FOXA3
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PROVIDER: PRJNA842656 | ENA |
REPOSITORIES: ENA
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Project description:Plasticity of differentiated cells has been proved by nuclear transfer, induced pluripotent cells and transdifferentiation. Here we show that by transduction of 3 factors (FOXA3, HNF1A and HNF4A), human fetal fibroblasts can be converted to hepatocyte-like cells (hiHep cells), expressing hepatic marker genes, and acquiring many mature hepatocyte functions in vitro and in vivo. Human fetal fibroblasts (HFF) were tranfected with 3 liver enriched transcription factors (FOXA3, HNF1A, HNF4A), and converted to hepatocyte-like cells (hiHep cells). HFF and primary human hepatocytes (PHH) serve as control.
2014-03-06 | E-GEOD-42643 | biostudies-arrayexpress
Project description:We have generated an immortal fibroblast-derived cell line without malignant traits capable of being efficiently and easily reprogrammable into hepatocyte-like cells under standard culture conditions by combining hTERT expression and a polycistronic vector inducible with doxycycline.
2023-03-03 | GSE204867 | GEO
Project description:Plasticity of differentiated cells has been proved by nuclear transfer, induced pluripotent cells and transdifferentiation. Here we show that by transduction of 3 factors (FOXA3, HNF1A and HNF4A), human fetal fibroblasts can be converted to hepatocyte-like cells (hiHep cells), expressing hepatic marker genes, and acquiring many mature hepatocyte functions in vitro and in vivo.
2014-03-06 | GSE42643 | GEO
Project description:The transcriptional regulation of drug-metabolizing enzymes and transporters (here collectively referred to as DMEs) in the developing proximal tubule is not well understood. As in the liver, DME regulation in the PT may be mediated through nuclear receptors which are thought to “sense” deviations from homeostasis by being activated by ligands, some of which are handled by DMEs, including drug transporters. Systems analysis of transcriptomic data during kidney development predicted a set of upstream transcription factors, including Hnf4a and Hnf1a, as well as Nr3c1 (Gr), Nfe2l2 (Nrf2), Ppara, and Tp53. Motif analysis of cis-regulatory further suggested that Hnf4a and Hnf1a are the main transcriptional regulators in the PT. Available expression data from tissue-specific Hnf4a KO tissues revealed that distinct subsets of DMEs were regulated by Hnf4a in a tissue-specific manner. ChIP-seq was performed to characterize the PT-specific binding sites of Hnf4a in rat kidneys at three developmental stages (prenatal, immature, adult), which further supported a major role for Hnf4a in regulating PT gene expression, including DMEs. In ex vivo kidney organ culture, an antagonist of Hnf4a (but not a similar inactive compound) led to predicted changes in DME expression, including among others Fmo1, Cyp2d2, Cyp2d4, Nqo2, as well as organic cation transporters and organic anion transporters Slc22a1(Oct1), Slc22a2 (Oct2), Slc22a6 (Oat1), Slc22a8(Oat3), and Slc47a1(Mate1). Conversely, overexpression of Hnf1a and Hnf4a in primary mouse embryonic fibroblasts (MEFs), sometimes considered a surrogate for mesenchymal stem cells, induced expression of several of these proximal tubule DMEs, as well as epithelial markers and a PT-specific brush border marker Ggt1. These cells had organic anion transporter function. Taken together, the data strongly supports a critical role for HNF4a and Hnf1a in the tissue-specific regulation of drug handling and differentiation toward a PT cellular identity. Hnf4a binding was examined in rat kidneys at three timepoints (E20, P13 and Adult) and p300 binding was examined in adult rat kidney cortex tissue using ChIP-seq. Four corresponding input DNA samples were used as controls for peak calling.
2014-01-01 | E-GEOD-50815 | biostudies-arrayexpress
Project description:The transcriptional regulation of drug-metabolizing enzymes and transporters (here collectively referred to as DMEs) in the developing proximal tubule is not well understood. As in the liver, DME regulation in the PT may be mediated through nuclear receptors which are thought to “sense” deviations from homeostasis by being activated by ligands, some of which are handled by DMEs, including drug transporters. Systems analysis of transcriptomic data during kidney development predicted a set of upstream transcription factors, including Hnf4a and Hnf1a, as well as Nr3c1 (Gr), Nfe2l2 (Nrf2), Ppara, and Tp53. Motif analysis of cis-regulatory further suggested that Hnf4a and Hnf1a are the main transcriptional regulators in the PT. Available expression data from tissue-specific Hnf4a KO tissues revealed that distinct subsets of DMEs were regulated by Hnf4a in a tissue-specific manner. ChIP-seq was performed to characterize the PT-specific binding sites of Hnf4a in rat kidneys at three developmental stages (prenatal, immature, adult), which further supported a major role for Hnf4a in regulating PT gene expression, including DMEs. In ex vivo kidney organ culture, an antagonist of Hnf4a (but not a similar inactive compound) led to predicted changes in DME expression, including among others Fmo1, Cyp2d2, Cyp2d4, Nqo2, as well as organic cation transporters and organic anion transporters Slc22a1(Oct1), Slc22a2 (Oct2), Slc22a6 (Oat1), Slc22a8(Oat3), and Slc47a1(Mate1). Conversely, overexpression of Hnf1a and Hnf4a in primary mouse embryonic fibroblasts (MEFs), sometimes considered a surrogate for mesenchymal stem cells, induced expression of several of these proximal tubule DMEs, as well as epithelial markers and a PT-specific brush border marker Ggt1. These cells had organic anion transporter function. Taken together, the data strongly supports a critical role for HNF4a and Hnf1a in the tissue-specific regulation of drug handling and differentiation toward a PT cellular identity.
2014-01-01 | GSE50815 | GEO
Project description:To determine the downstream regulatory network of HNF4A and HNF1A, two transcription factors that play important roles in the pancreas and liver and that are associated with diabetes, we generated a comprehensive genome-wide map of the binding targets of HNF4A and HNF1A in hiPSC-derived pancreatic and hepatic cells and relevant cell lines using ChIP-Seq and molecular validation. We report binding targets of HNF4A and HNF1A that map to both known and novel gene promoters, that are common or differentially bound across different cell types and developmental stages. Overall, the detailed characterisation of the regulatory roles of HNF4A and HNF1A in pancreatic beta cells and hepatic cells will potentially shed light on how dysregulation of these factors can contribute to altered tissue development and function, and thus pathogenesis of both monogenic diabetes and T2D.
2024-02-29 | GSE206240 | GEO
Project description:Gene expression of mouse hepatoblasts (HBs) expressing IDH1 WT, IDH1 R132C, IDH2 WT, R172K and empty vector controls (N=2 cultures for each condition) grown on collagen-coated plates and IDH1 R132C and empty vector controls on uncoated plates were evaluated using Affymetrix Mouse 430Av2 DNA microarrays that were processed at the Dana-Farber Cancer Institute core facility (http://macf-web.dfci.harvard.edu/) using their standard protocol. Mutations in Isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly primary liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert alphaketoglutarate (aKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple aKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks primary liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF4a, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models (GEMMs) expressing mutant IDH in the adult liver show aberrant response to hepatic injury, characterized by HNF4a silencing, impaired hepatocyte differentiation and markedly elevated levels of cell proliferation. Moreover, mutant IDH and activated Kras, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis and present a novel GEMM of IDH-driven malignancy. Gene expression of HBs expressing IDH1 WT, IDH1 R132C, IDH2 WT, R172K and empty vector controls under a doxycycline-inducible system (N=2 cultures for each condition) grown on collagen-coated plates and IDH1 R132C and empty vector controls on uncoated plates were evaluated using Affymetrix Mouse 430Av2 DNA microarrays.
2014-04-30 | E-GEOD-57002 | biostudies-arrayexpress
Project description:Here, we use chromatin immunoprecipitation combined with promoter microarrays to identify the genes occupied by the transcriptional regulators HNF1a, HNF4a and HNF6, together with RNA polymerase II, in human liver and pancreatic islets.
2004-07-15 | E-MEXP-68 | biostudies-arrayexpress
Project description:In order to elucidate an anticancer function of some hepatic transcription factors (TFs), we induced the three hepatic TFs: HNF1A, HNF4A, and FOXA3, into a hepatocellular carcinoma cell line, HepG2, with some combination.
2018-10-02 | GSE115423 | GEO
Project description:Generating insulin-producing β-cells from human induced pluripotent stem cells is a promising cell replacement therapy aimed at improving or curing certain forms of diabetes. Nevertheless, despite important recent advances, the efficient production of functionally mature β-cells is yet to be achieved, with most current differentiation protocols generating a heterogeneous population comprising of subpopulation of cells expressing different islet hormones, including hybrid polyhormonal entities. A solution to this issue is transplanting end-stages differentiating cells into living hosts, which was demonstrated to majorly improve β-cell maturation. Yet, to date, the cellular and molecular mechanisms underlying the transplanted cells response to the in vivo environment exposure was not yet properly characterized. Here we use global proteomics and large-scale imaging techniques aimed at demultiplexing and filtering cellular processes and molecular signatures modulated by the immediate in vivo effect. We show that in vivo exposure swiftly confines in vitro generated human pancreatic progenitors to single hormone expression. The global proteome landscape of the transplanted cells was closer to the one presented by native human islets, especially in regard to energy metabolism and redox balance. Moreover our study indicates a possible link between these processed and certain epigenetic regulators involved in maintenance and propagation of the islet cells identity. Pathway analysis predicted HNF1A and HNF4A as key regulators controlling the in vivo islet-promoting response, with experimental evidence confirming their involvement in confining islet cell identity. To our knowledge this is the first study demultiplexing the immediate response of the transplanted pancreatic progenitors to in vivo exposure.
2020-02-12 | PXD015955 | Pride