RNA-sequencing in human primary hepatocytes lacking NREP
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE229455 | GEO | 2023/06/26
REPOSITORIES: GEO
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Project description:To evaluate the global signaling changes induced by Neuronal Regeneration Related Protein (NREP) downregulation, we employed antibody-microarrays in human primary hepatocytes lacking NREP.
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Project description:To evaluate the global transcriptomic changes induced by Neuronal Regeneration Related Protein (NREP) downregulation, we employed RNA-sequencing in HepG2 cells lacking NREP. Enriched pathway analyses of upregulated genes revealed pathways involved in cholesterol synthesis, fatty acid metabolism, NAFLD and PI3K-250 AKT signaling. In contrast, enriched downregulated genes included those for membrane trafficking, non-sense mediated decay, glucagon signaling, and cell-cycle. Differentially expressed genes included HMGCR (cholesterol synthesis) and TGFBR1 (TGF-β signaling and fibrosis).
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Project description:BACKGROUND & AIMS: Thirty to ninety percent of hepatocytes contain whole genome duplications, making it imperative to understand the fates and functions of these polyploid cells and how they affect development of liver disease. An important question is how polyploid cells respond to chronic proliferative demands, which are characteristic of liver diseases, but a challenging situation for cells with multiple genomes. METHODS: To interrogate liver polyploidy, we employed a mouse with reversible ANLN ( Anillin actin binding protein) knockdown that drives hepatocyte polyploidization in a doxycycline inducible fashion. Diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) were used to induce chronic liver damage and hepatocellular carcinoma (HCC). We performed partial hepatectomies to test regeneration and RNA-seq to assess gene expression changes. Lineage tracing was used to rule out repopulation from non-hepatocyte sources. In vivo imaging of mitotic hepatocytes estimated the frequency of aneuploidy during regeneration, and exome sequencing of 54 human cirrhotic nodules was used to quantify aneuploidy. RESULTS: Hepatocytes from mice given chronic CCl4 alone showed significant increases in ploidy. Super-polyploid mice with 97% polyploid hepatocytes, due to induced knockdown of Anln , were almost completely protected from tumorigenesis induced by DEN and chronic CCl4 . The protection was not associated with differences in regenerative capacity, tissue fitness, gene regulation, or mitotic errors. Regenerative contributions from a non-hepatocyte population were ruled out using lineage tracing, confirming that polyploids can replenish tissues during chronic damage. No lagging chromosomes or micronuclei were found in mitotic polyploid cells and there was no evidence of chromosomal copy number variations in 54 nodules, suggesting that aneuploidy is not a common outcome of polyploid cell divisions. CONCLUSION: During chronic injury, polyploid hepatocytes readily divide and regenerate while being buffered from tumor suppressor loss and tumorigenesis. Therapeutic strategies to increase numbers of polypoid hepatocytes could prevent cancer while preserving regeneration.
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