The CCCTC-binding factor CTCF represses hepatitis B virus enhancer I and regulates viral transcription
| Autor: | Peter A C Wing, Jack Ferguson, Xiaodong Zhuang, Sophia Begum, Barbara Testoni, Fleur Chapus, Jane A. McKeating, Guillaume Giraud, James M. Harris, Peter Balfe, Valentina D'Arienzo, Joanna L Parish, Adam Claydon |
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| Rok vydání: | 2020 |
| Předmět: |
Epigenomics
Gene Expression Regulation Viral CCCTC-Binding Factor Chromatin Immunoprecipitation Hepatitis B virus Immunology Insulator (genetics) medicine.disease_cause Virus Replication Microbiology Article Cell Line Viral Transcription 03 medical and health sciences 0302 clinical medicine Transcription (biology) Virology medicine HBV Humans Enhancer 030304 developmental biology 0303 health sciences Binding Sites biology epigenetics 030306 microbiology cccDNA Hep G2 Cells biology.organism_classification Hepatitis B CTCF digestive system diseases Chromatin Cell biology 3. Good health Enhancer Elements Genetic Hepadnaviridae DNA Viral Mutation RNA Viral 030211 gastroenterology & hepatology transcription insulation transcription regulation Chromatin immunoprecipitation |
| Zdroj: | Cellular microbiology |
| ISSN: | 1462-5822 |
| Popis: | Hepatitis B virus (HBV) infection is of global importance with over 2 billion people exposed to the virus during their lifetime and at risk of progressive liver disease, cirrhosis and hepatocellular carcinoma. HBV is a member of the hepadnaviridae family that replicates via episomal copies of a covalently closed circular DNA (cccDNA) genome. The chromatinization of this small viral genome, with overlapping open reading frames and regulatory elements, suggests an important role for epigenetic pathways to regulate viral transcription. The chromatin-organising transcriptional insulator protein CCCTC-binding factor (CTCF) has been reported to regulate transcription in a diverse range of viruses. We identified two conserved CTCF binding sites in the HBV genome within Enhancer I and chromatin immunoprecipitation (ChIP) analysis demonstrated an enrichment of CTCF binding to integrated or episomal copies of the viral genome. siRNA knockdown of CTCF results in a significant increase in pre-genomic RNA levels in de novo infected HepG2 cells and those supporting episomal HBV DNA replication. Furthermore, mutation of these sites in HBV DNA minicircles abrogated CTCF binding and increased pre-genomic RNA levels, providing evidence of a direct role for CTCF in repressing HBV transcription.IMPORTANCEHepatitis B virus (HBV) is a global cause of liver disease. At least 300 million individuals are chronically infected with HBV, frequently leading to life-threatening liver cirrhosis and cancer. Following viral entry, HBV DNA enters the nucleus and is bound by histones that are subject to epigenetic modification. The HBV genome contains two enhancer elements that stimulate viral transcription but the interplay between the viral enhancers and promoters is not fully understood. We have identified the host cell protein CCCTC binding factor (CTCF) as a repressor of HBV gene expression. CTCF binds to the HBV genome within Enhancer I and represses transcription of pre-genomic RNA. These findings provide new insights into how HBV transcription is regulated and show a new role for CTCF as a transcriptional insulator by associating with the viral genome between Enhancer I and the downstream basal core promoter. |
| Databáze: | OpenAIRE |
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