Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
Department of Engineering, Campus Bio-Medico University, Rome, Italy
Cancer Research Center of Lyon (CRCL), UMR Inserm U1052 / CNRS 5286, Lyon, France
Department of Physics and Chemistry - Emilio Segre', University of Palermo, Palermo, Italy
SAFU Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Department of Internal Medicine (DMISM), Sapienza University, Rome, Italy
Correspondence to Dr Francesca Guerrieri, Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia Center for Life Nano Science, Roma 00162, Italy; [email protected]; Professor Massimo Levrero, Cancer Research Center of Lyon (CRCL), Lyon, France; [email protected]
Abstract
Objective The HBV HBx regulatory protein is required for transcription from the covalently closed circular DNA (cccDNA) minichromosome and affects the epigenetic control of both viral and host cellular chromatin.
Design We explored, in relevant cellular models of HBV replication, the functional consequences of HBx interaction with DLEU2, a long non-coding RNA (lncRNA) expressed in the liver and increased in human hepatocellular carcinoma (HCC), in the regulation of host target genes and the HBV cccDNA.
Results We show that HBx binds the promoter region, enhances the transcription and induces the accumulation of DLEU2 in infected hepatocytes. We found that nuclear DLEU2 directly binds HBx and the histone methyltransferase enhancer of zeste homolog 2 (EZH2), the catalytic active subunit of the polycomb repressor complex 2 (PRC2) complex. Computational modelling and biochemical evidence suggest that HBx and EZH2 share two preferential binding sites in DLEU2 intron 1. HBx and DLEU2 co-recruitment on the cccDNA displaces EZH2 from the viral chromatin to boost transcription and viral replication. DLEU2-HBx association with target host promoters relieves EZH2 repression and leads to the transcriptional activation of a subset of EZH2/PRC2 target genes in HBV-infected cells and HBV-related HCCs.
Conclusions Our results highlight the ability of HBx to bind RNA to impact on the epigenetic control of both viral cccDNA and host genes and provide a new key to understand the role of DLEU2 and EZH2 overexpression in HBV-related HCCs and HBx contribution to hepatocytes transformation. http://creativecommons.org/licenses/by-nc/4.0/
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