Control of cccDNA function in hepatitis B virus infection

Levrero, Massimo; Pollicino, Teresa; Petersen, Jörg; Belloni, Laura; Raimondo, Giovanni; Dandri, Maura

doi:10.1016/j.jhep.2009.05.022

Cited by 490 publications

(401 citation statements)

References 89 publications

(116 reference statements)

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“…HBx has also been shown to modulate chromatin dynamics in HCC cells and tissues. HBx binds several nuclear proteins involved in the regulation of transcription, including components of the basal transcriptional machinery (RPB5, TFIIB, TBP, TFIIH), coactivators (CBP, p300, and PCAF), and transcription factors (ATF/CREB, ATF3, c/EBP, NF-IL-6, Ets, Egr, SMAD4, Oct1, RXR receptor, p53) (14,34). HBx is bound in vivo to the promoters of a number of CREB-regulated genes and favors transcription by increasing the amount of CBP and p300 recruited on the same promoters (17).…”

Section: Discussionmentioning

confidence: 99%

Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function

Belloni

Pollicino

Nicola

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

434

503

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HBV cccDNA, the template for transcription of all viral mRNAs, accumulates in the nucleus of infected cells as a stable episome organized into minichromosomes by histones and non-histone viral and cellular proteins. Using a cccDNA-specific chromatin immunoprecipitation (ChIP)-based quantitative assay, we have previously shown that transcription of the HBV minichromosome is regulated by epigenetic changes of cccDNA-bound histones and that modulation of the acetylation status of cccDNA-bound H3/H4 histones impacts on HBV replication. We now show that the cellular histone acetyltransferases CBP, p300, and PCAF/GCN5, and the histone deacetylases HDAC1 and hSirt1 are all recruited in vivo onto the cccDNA. We also found that the HBx regulatory protein produced in HBV replicating cells is recruited onto the cccDNA minichromosome, and the kinetics of HBx recruitment on the cccDNA parallels the HBV replication. As expected, an HBV mutant that does not express HBx is impaired in its replication, and exogenously expressed HBx transcomplements the replication defects. p300 recruitment is severely impaired, and cccDNA-bound histones are rapidly hypoacetylated in cells replicating the HBx mutant, whereas the recruitment of the histone deacetylases hSirt1 and HDAC1 is increased and occurs at earlier times. Finally, HBx mutant cccDNA transcribes significantly less pgRNA. Altogether our results further support the existence of a complex network of epigenetic events that influence cccDNA function and HBV replication and identify an epigenetic mechanism (i.e., to prevent cccDNA deacetylation) by which HBx controls HBV replication.histone acetylation ͉ HATs ͉ HDACs H epatitis B virus (HBV) infection is a major health problem, with Ϸ400 million people chronically infected worldwide who are at high risk of developing liver cirrhosis and hepatocellular carcinoma (HCC) (1). The epidemiological evidence linking HBV infection to HCC is very strong, and despite the mechanisms underlying HBV-associated carcinogenesis remain to be fully defined, a growing number of studies support a direct role of HBV in the process (2-5). The HBV-encoded regulatory protein hepatitis B virus X protein (HBx) is thought to contribute to HBV oncogenicity (5, 6). HBx transforms SV40-immortalized murine hepatocytes, induces cell cycle progression within the regenerating liver, causes liver cancer in some transgenic mice, and acts as a cofactor to accelerate cancer development in other mouse models (6-11). HBx is a 154-amino acid protein with an N-terminal negative regulatory domain and C-terminal transactivation or coactivation domain that has been detected both in the cytoplasm and in the nuclei of infected hepatocytes (6,12,13). Studies in transfected cells have shown that HBx expression affects several cellular functions such as cytoplasmic calcium regulation, cell signaling, transcription, cell proliferation, DNA repair, and apoptosis (11, 13-16). To perform its multiple functions, HBx interacts with many cellular partners including the tumor suppressor p53,...

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Section: Discussionmentioning

confidence: 99%

Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function

Belloni

Pollicino

Nicola

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

434

503

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show abstract

“…221,222 The regulation of the intrahepatic pool of cccDNA involves several factors including the dynamics of infection in the liver and the intrahepatic antiviral immune response. 223 Furthermore, cccDNA transcriptional activity is controlled by fine epigenetic regulation which can involve viral and host factors. 13,224 Besides the need for standardized assays, the main limitation of cccDNA studies is the requirement of liver biopsy; thus surrogate biomarkers are being evaluated (see below).…”

Section: New Biomarkers Of Hbv Infectionmentioning

confidence: 99%

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

Lampertico¹,

Agarwal²,

Berg³

et al. 2017

Journal of Hepatology

4,184

3,081

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“…HBV integration can cause microdeletions in the host DNA on positions that may involve cancer relevant genes such as MAPK and TERT [27] . HBV can also persist in the liver for many years in the socalled cccDNA form, the intermediate form required for viral reproduction [28] . Through this mechanism, there will be a continous immunological respons on newly produced viral antigens in these chronically infected patients that can contribute to cellular damage and malignant transformation (see also oxidative stress).…”

Section: Hepatitis B Virusmentioning

confidence: 99%

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

Severi¹,

Malenstein²,

Verslype³

et al. 2010

Acta Pharmacol Sin

157

125

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Control of cccDNA function in hepatitis B virus infection

Cited by 490 publications

References 89 publications

Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function

Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function

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

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

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