title: IL6 Inhibits HBV Transcription by Targeting the Epigenetic Control of the Nuclear cccDNA Minichromosome.
abstract: The HBV covalently closed circular DNA (cccDNA) is organized as a mini-chromosome in the nuclei of infected hepatocytes by histone and non-histone proteins. Transcription from the cccDNA of the RNA replicative intermediate termed pre-genome (pgRNA), is the critical step for genome amplification and ultimately determines the rate of HBV replication. Multiple evidences suggest that cccDNA epigenetic modifications, such as histone modifications and DNA methylation, participate in regulating the transcriptional activity of the HBV cccDNA. Inflammatory cytokines (TNFα, LTβ) and the pleiotropic cytokine interleukin-6 (IL6) inhibit hepatitis B virus (HBV) replication and transcription. Here we show, in HepG2 cells transfected with linear HBV monomers and HBV-infected NTCP-HepG2 cells, that IL6 treatment leads to a reduction of cccDNA-bound histone acetylation paralleled by a rapid decrease in 3.5kb/pgRNA and subgenomic HBV RNAs transcription without affecting cccDNA chromatinization or cccDNA levels. IL6 repressive effect on HBV replication is mediated by a loss of HNF1α and HNF4α binding to the cccDNA and a redistribution of STAT3 binding from the cccDNA to IL6 cellular target genes.
authors.affiliation: Dept of Internal Medicine-DMISM, Sapienza University, Rome, Italy.
authors.forename: Gianna Aurora
authors.initials: GA
authors.lastname: Palumbo
authors.affiliation: Dept of Internal Medicine-DMISM, Sapienza University, Rome, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Scisciani
authors.affiliation: Dept of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Pediconi
authors.affiliation: Dept of Internal Medicine-DMISM, Sapienza University, Rome, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Lupacchini
authors.affiliation: INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France.
authors.forename: Dulce
authors.initials: D
authors.lastname: Alfalate
authors.affiliation: Center for Life NanoSciences (CLNS), IIT-Sapienza, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Guerrieri
authors.affiliation: Dept of Internal Medicine-DMISM, Sapienza University, Rome, Italy.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Calvo
authors.affiliation: Dept of Internal Medicine-DMISM, Sapienza University, Rome, Italy.|Center for Life NanoSciences (CLNS), IIT-Sapienza, Rome, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Salerno
authors.affiliation: Dept of Internal Medicine-DMISM, Sapienza University, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Cocco
authors.affiliation: Dept of Internal Medicine-DMISM, Sapienza University, Rome, Italy.|INSERM U1052, Cancer Research Center of Lyon (CRCL), Lyon, France.|Center for Life NanoSciences (CLNS), IIT-Sapienza, Rome, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Levrero
authors.affiliation: Dept of Internal Medicine-DMISM, Sapienza University, Rome, Italy.|Center for Life NanoSciences (CLNS), IIT-Sapienza, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Belloni
mesh_terms: D019175:DNA Methylation / Q000235:genetics; D004270:DNA, Circular / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D044127:Epigenesis, Genetic; D015967:Gene Expression Regulation, Viral; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000235:genetics* / Q000472:pathogenicity; D019694:Hepatitis B, Chronic / Q000235:genetics* / Q000821:virology; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics; D014158:Transcription, Genetic; D014779:Virus Replication / Q000235:genetics*
chemical_list: D004270:DNA, Circular; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D006657:Histones; C508600:IL6 protein, human; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C100808:pgRNA; D012313:RNA