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HNF4a Mediated Formation of Hepatic Progentiors [array expression data set]

ABSTRACT: HNF4a Mediated Formation of Hepatic Progentiors [array expression data set]

PROVIDER: PRJNA413300 | ENA |

REPOSITORIES: ENA

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HNF4a Mediated Formation of Hepatic Progentiors [array expression data set]

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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HNF4a regulates hepatic peroxisomal biogenesis and fatty acid elongation during the thermogenic response

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Comprehensive characterisation of HNF4A and HNF1A genomic targets in pancreatic beta cells and hepatic cells reveals common and tissue-specific pathways and genes

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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:Of 610 miRNAs, expression of 24 and 19 miRNAs was down-regulated or up-regulated more than 2-fold in Hnf4aÎH mice as compared to control (Hnf4af/f) mice In the study presented here, in order to identifiy the target genes for hepatic HNF4a, hepatic expression profiles of a total of 610 unique miRNA genes in Hnf4aÎH mice were investigated as compared with Hnf4af/f mice

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