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      Hepatitis B protein HBx binds the DLEU2 lncRNA to sustain cccDNA and host cancer-related gene transcription

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          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.

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          Most cited references56

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          EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.

          Hepatitis B virus (HBV) infection remains a global public health problem with changing epidemiology due to several factors including vaccination policies and migration. This Clinical Practice Guideline presents updated recommendations for the optimal management of HBV infection. Chronic HBV infection can be classified into five phases: (I) HBeAg-positive chronic infection, (II) HBeAg-positive chronic hepatitis, (III) HBeAg-negative chronic infection, (IV) HBeAg-negative chronic hepatitis and (V) HBsAg-negative phase. All patients with chronic HBV infection are at increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC), depending on host and viral factors. The main goal of therapy is to improve survival and quality of life by preventing disease progression, and consequently HCC development. The induction of long-term suppression of HBV replication represents the main endpoint of current treatment strategies, while HBsAg loss is an optimal endpoint. The typical indication for treatment requires HBV DNA >2,000IU/ml, elevated ALT and/or at least moderate histological lesions, while all cirrhotic patients with detectable HBV DNA should be treated. Additional indications include the prevention of mother to child transmission in pregnant women with high viremia and prevention of HBV reactivation in patients requiring immunosuppression or chemotherapy. The long-term administration of a potent nucleos(t)ide analogue with high barrier to resistance, i.e., entecavir, tenofovir disoproxil or tenofovir alafenamide, represents the treatment of choice. Pegylated interferon-alfa treatment can also be considered in mild to moderate chronic hepatitis B patients. Combination therapies are not generally recommended. All treated and untreated patients should be monitored for treatment response and adherence, and the risk of progression and development of complications. HCC remains the major concern for treated chronic hepatitis B patients. Several subgroups of patients with HBV infection require specific focus. Future treatment strategies to achieve 'cure' of disease and new biomarkers are discussed.
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            Molecular mechanisms of long noncoding RNAs.

            Long noncoding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. Here we discuss the emerging archetypes of molecular functions that lncRNAs execute-as signals, decoys, guides, and scaffolds. For each archetype, examples from several disparate biological contexts illustrate the commonality of the molecular mechanisms, and these mechanistic views provide useful explanations and predictions of biological outcomes. These archetypes of lncRNA function may be a useful framework to consider how lncRNAs acquire properties as biological signal transducers and hint at their possible origins in evolution. As new lncRNAs are being discovered at a rapid pace, the molecular mechanisms of lncRNAs are likely to be enriched and diversified. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis

              Large intervening noncoding RNAs (lincRNAs) are pervasively transcribed in the genome1, 2, 3 yet their potential involvement in human disease is not well understood4,5. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodeling activities6,7,8. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumors and metastases, and HOTAIR expression level in primary tumors is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb Repressive Complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings suggest that lincRNAs play active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
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                Author and article information

                Journal
                Gut
                Gut
                gutjnl
                gut
                Gut
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0017-5749
                1468-3288
                November 2020
                29 February 2020
                : 69
                : 11
                : 2016-2024
                Affiliations
                [1 ] departmentCenter for Life NanoScience@Sapienza , Istituto Italiano di Tecnologia , Rome, Italy
                [2 ] departmentDepartment of Engineering , Campus Bio-Medico University , Rome, Italy
                [3 ] departmentCancer Research Center of Lyon (CRCL) , UMR Inserm U1052 / CNRS 5286 , Lyon, France
                [4 ] departmentDepartment of Physics and Chemistry - Emilio Segre' , University of Palermo , Palermo, Italy
                [5 ] departmentSAFU Unit , IRCCS Regina Elena National Cancer Institute , Rome, Italy
                [6 ] departmentDepartment of Internal Medicine (DMISM) , Sapienza University , Rome, Italy
                Author notes
                [Correspondence to ] Dr Francesca Guerrieri, Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia Center for Life Nano Science, Roma 00162, Italy; fraguerrieri@ 123456gmail.com ; Professor Massimo Levrero, Cancer Research Center of Lyon (CRCL), Lyon, France; massimo.levrero@ 123456inserm.fr

                DS and LC are joint first authors.

                Author information
                http://orcid.org/0000-0002-8278-7075
                http://orcid.org/0000-0001-8594-9837
                http://orcid.org/0000-0002-4978-0875
                http://orcid.org/0000-0002-2021-4394
                Article
                gutjnl-2019-319637
                10.1136/gutjnl-2019-319637
                7569396
                32114505
                0d26825f-44de-4ba4-a2bb-872db4d6e7d0
                © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 14 August 2019
                : 29 January 2020
                : 29 January 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001665, Agence Nationale de la Recherche;
                Award ID: ANR@RACTION 2014-2019
                Funded by: FundRef http://dx.doi.org/10.13039/100010677, H2020 Health;
                Award ID: EU project 667273 HEP-CAR
                Funded by: FundRef http://dx.doi.org/10.13039/501100003323, Agence Nationale de Recherches sur le Sida et les Hepatites Virales;
                Award ID: n. ECTZ8323; n. ECTZ27696; n. ECTZ66014
                Categories
                Hepatology
                1506
                2312
                Original research
                Custom metadata
                unlocked

                Gastroenterology & Hepatology
                hepatocellular carcinoma,hepatitis b,liver
                Gastroenterology & Hepatology
                hepatocellular carcinoma, hepatitis b, liver

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