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

Gut - Tập 69 Số 11 - Trang 2016-2024 - 2020
Debora Salerno1, Letizia Chiodo2, Vincenzo Alfano3, Océane Floriot3, Grazia Cottone4, Alexia Paturel3, Matteo Pallocca5, Marie‐Laure Plissonnier3, S. Jeddari6, Laura Belloni6, Mirjam B. Zeisel3, Massimo Levrero3,6, Francesca Guerrieri3,1
1Istituto Italiano di Tecnologia
2Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome
3Centre de recherche en cancérologie de Lyon
4Università degli studi di Palermo - University of Palermo
5National Cancer Institute Regina Elena, Rome, Italy
6Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome]

Tóm tắt

ObjectiveThe 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.DesignWe 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.ResultsWe 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.ConclusionsOur 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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Tài liệu tham khảo

World Health Organization . Global hepatitis report 2017, 2017. Available: http://www.who.int/iris/handle/10665/255016

10.1016/S0140-6736(15)61412-X

10.1016/S0140-6736(16)30579-7

10.1002/hep.29323

10.1016/j.jhep.2017.03.021

Mason, 2016, Hbv DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant, Gastroenterology, 151, 986, 10.1053/j.gastro.2016.07.012

10.1055/s-0037-1606212

10.1053/j.gastro.2006.01.001

10.1038/nature17170

10.1073/pnas.0908365106

10.1016/j.jhep.2015.06.023

Guerrieri F , Belloni L , D'Andrea D , et al . Genome-Wide identification of direct HBx genomic targets. BMC Genomics 2017;18:184. doi:10.1186/s12864-017-3561-5

Moyo, 2016, The role of long non-coding RNAs in hepatitis B virus-related hepatocellular carcinoma, Virus Res, 212, 103, 10.1016/j.virusres.2015.07.025

10.1016/j.molcel.2011.08.018

Liu W , Ding C . Roles of lncRNAs in viral infections. Front Cell Infect Microbiol 2017;7:205. doi:10.3389/fcimb.2017.00205

10.1126/science.aao0409

10.1016/j.molcel.2010.12.011

10.1038/nsmb.2315

10.1038/nature09784

10.1101/gad.1886410

10.1016/j.cell.2014.10.019

10.1016/j.jmb.2016.10.012

10.1136/gut.2010.231993

10.1038/nchembio.1331

Lavarone E , Barbieri CM , Pasini D . Dissecting the role of H3K27 acetylation and methylation in PRC2 mediated control of cellular identity. Nat Commun 2019;10:1679. doi:10.1038/s41467-019-09624-w

10.1073/pnas.1308953111

Li, 2017, Trim28 interacts with EZH2 and SWI/SNF to activate genes that promote mammosphere formation, Oncogene, 36, 2991, 10.1038/onc.2016.453

Yang Y , Chen L , Gu J , et al . Recurrently deregulated lncRNAs in hepatocellular carcinoma. Nat Commun 2017;8:14421. doi:10.1038/ncomms14421

Peng L , Paulson A , Li H , et al . Developmental programming of long non-coding RNAs during postnatal liver maturation in mice. PLoS One 2014;9:e114917. doi:10.1371/journal.pone.0114917

Giulietti, 2018, Lncrna co-expression network analysis reveals novel biomarkers for pancreatic cancer, Carcinogenesis, 39, 1016, 10.1093/carcin/bgy069

10.1136/gutjnl-2014-308483

10.1016/j.yexcr.2009.07.001

10.1038/nature08975

Hu J-J , Song W , Zhang S-D , et al . HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling. Sci Rep 2016;6:23521. doi:10.1038/srep23521

10.1038/onc.2015.122

10.1038/nmeth.4100

10.1093/bioinformatics/btn334

10.1016/j.jmb.2015.09.014

Antonysamy S , Condon B , Druzina Z , et al . Structural context of disease-associated mutations and putative mechanism of autoinhibition revealed by X-ray crystallographic analysis of the EZH2-SET domain. PLoS One 2013;8:e84147. doi:10.1371/journal.pone.0084147

10.3390/v6114683

10.1016/j.jmb.2007.07.004

Walia RR , Xue LC , Wilkins K , et al . RNABindRPlus: a predictor that combines machine learning and sequence homology-based methods to improve the reliability of predicted RNA-binding residues in proteins. PLoS One 2014;9:e97725. doi:10.1371/journal.pone.0097725

Wass MN , Fuentes G , Pons C , et al . Towards the prediction of protein interaction partners using physical docking. Mol Syst Biol 2011;7:469. doi:10.1038/msb.2011.3

10.1038/nsmb.1719

10.1016/j.jhep.2011.02.015

10.1002/hep.28698

10.1002/hep.29133

10.1016/j.cellsig.2014.08.008

Chen W-xian , Cheng L , Xu L-yun , et al . Bioinformatics analysis of prognostic value of TRIM13 gene in breast cancer. Biosci Rep 2019;39.doi:10.1042/BSR20190285

Slagle BL , Bouchard MJ . Hepatitis B virus X and regulation of viral gene expression. Cold Spring Harb Perspect Med 2016;6:a021402. doi:10.1101/cshperspect.a021402

10.1016/j.jhep.2017.05.008

10.1002/hep.25781

10.1016/j.molcel.2014.12.009

10.1101/gr.197632.115

10.1016/j.molcel.2014.12.017

10.1038/s41594-019-0197-y

10.1016/j.molcel.2017.02.003

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Gut

Tập 69 Số 11

2016-2024

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