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Virus de l’Hépatite B et transcription cellulaire : impact de la protéine HBx et de ses interactions avec les ARNs non-codants

Abstract : Hepatitis B virus (HBV) remains a major health problem worldwide despite the availability of the vaccine. No cure is available for the 240 million peoples chronically infected with HBV that are at risk to develop liver cirrhosis and hepatocellular carcinoma (HCC). Viral suppression, achieved by long term treatment with nucleotides analogues (NUCs), impacts on liver fibrosis and prevents liver decompensation but HCC risk is not reduced in the first 5 years of treatment. HBV is a small hepatotropic virus with a partially double strand DNA (rcDNA) genome. After hepatocyte infection the rcDNA is converted into the cccDNA episome that is then organized into a viral minichromosome that is the template for all viral transcripts and initiates replication. The hepatitis B x protein (HBx) is recruited on the cccDNA and is required to launch and maintain cccDNA transcription. HBx has also been shown to directly target cellular genes and this has been related to HCC development.We used a ChIP-Seq approach to determine the full repertoire of HBx genomic targets in HBV replicating cells. HBx targets include both protein coding genes and ncRNA (75 miRNAs and 34 lncRNAs). We showed that HBx represses a subset of miRNAs that would negatively regulate viral replication (i.e. miR-24) and miRNAs involved in HCC development (i.e. miR-21). Among the HBx targeted lncRNAs we focused DLEU2, which is strongly upregulated in HBV infection and HCC. We further showed that DLEU2 binds both HBx the Ezh2 histone methyltransferase, the catalytic subunit of the repressive PRC2 complex. The interaction with DLEU2 and HBx re-wires Ezh2/PRC2 functions leading to the constitutive activation of a subset of Ezh2 target genes that are normally kept in a repressed state. We also showed that HBx interaction with DLEU2 occurs on the cccDNA minichromosome where it boosts HBV transcription/replication. Finally, we characterized by ATAC-Seq HBV imposed changes of chromatin accessibility in primary human hepatocytes
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Océane Floriot. Virus de l’Hépatite B et transcription cellulaire : impact de la protéine HBx et de ses interactions avec les ARNs non-codants. Virologie. Université de Lyon, 2018. Français. ⟨NNT : 2018LYSE1319⟩. ⟨tel-02077287⟩



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