Hepatitis B protein HBx binds the DLEU2 lncRNA to sustain cccDNA and host cancer-related gene transcription.
Carcinoma, Hepatocellular
/ etiology
Cell Culture Techniques
DNA, Circular
Enhancer of Zeste Homolog 2 Protein
/ metabolism
Hepatitis B virus
/ physiology
Hepatocytes
/ metabolism
Humans
Liver Neoplasms
/ etiology
RNA, Long Noncoding
/ metabolism
Trans-Activators
/ physiology
Viral Regulatory and Accessory Proteins
/ physiology
Virus Replication
/ physiology
hepatitis B
hepatocellular carcinoma
liver
Journal
Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
14
08
2019
revised:
29
01
2020
accepted:
29
01
2020
pubmed:
3
3
2020
medline:
17
4
2021
entrez:
2
3
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 32114505
pii: gutjnl-2019-319637
doi: 10.1136/gutjnl-2019-319637
pmc: PMC7569396
doi:
Substances chimiques
DLEU2 lncRNA, human
0
DNA, Circular
0
RNA, Long Noncoding
0
Trans-Activators
0
Viral Regulatory and Accessory Proteins
0
hepatitis B virus X protein
0
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2016-2024Informations de copyright
© 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.
Déclaration de conflit d'intérêts
Competing interests: None declared.
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