Genome-wide identification of direct HBx genomic targets

Guerrieri, Francesca; Belloni, Laura; D’Andrea, Daniel; Pediconi, Natalia; Pera, Loredana Le; Testoni, Barbara; Scisciani, C.; Floriot, Océane; Zoulim, Fabien; Tramontano, Anna; Levrero, Massimo

doi:10.1186/s12864-017-3561-5

Cited by 57 publications

(69 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hence rather than on direct binding to damaged DNA an HBx-mediated HBV linkage to DNA repair could be based on Smc5/6 degradation yet also on other, additional cellular HBx targets [163]. …”

Section: Evidence For a Connection Between Hbv And The Host Dna Damentioning

confidence: 99%

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

Schreiner

Nassal

2017

Viruses

View full text Add to dashboard Cite

Chronic hepatitis B virus (HBV) infection puts more than 250 million people at a greatly increased risk to develop end-stage liver disease. Like all hepadnaviruses, HBV replicates via protein-primed reverse transcription of a pregenomic (pg) RNA, yielding an unusually structured, viral polymerase-linked relaxed-circular (RC) DNA as genome in infectious particles. Upon infection, RC-DNA is converted into nuclear covalently closed circular (ccc) DNA. Associating with cellular proteins into an episomal minichromosome, cccDNA acts as template for new viral RNAs, ensuring formation of progeny virions. Hence, cccDNA represents the viral persistence reservoir that is not directly targeted by current anti-HBV therapeutics. Eliminating cccDNA will thus be at the heart of a cure for chronic hepatitis B. The low production of HBV cccDNA in most experimental models and the associated problems in reliable cccDNA quantitation have long hampered a deeper understanding of cccDNA molecular biology. Recent advancements including cccDNA-dependent cell culture systems have begun to identify select host DNA repair enzymes that HBV usurps for RC-DNA to cccDNA conversion. While this list is bound to grow, it may represent just one facet of a broader interaction with the cellular DNA damage response (DDR), a network of pathways that sense and repair aberrant DNA structures and in the process profoundly affect the cell cycle, up to inducing cell death if repair fails. Given the divergent interactions between other viruses and the DDR it will be intriguing to see how HBV copes with this multipronged host system.

show abstract

Section: Evidence For a Connection Between Hbv And The Host Dna Damentioning

confidence: 99%

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

Schreiner

Nassal

2017

Viruses

View full text Add to dashboard Cite

show abstract

“…Guerrieri et al 2017 identified and validated a role for HBx in regulating genes involved in endocytosis, predominantly members of the Ras-related in brain (Rab) family 9 . Anti-HBx chromatin immunoprecipitation studies identified HBx binding sites that included RAB1A, RAB2B and RAB5B promotors and none of the validated Rab genes were listed in our hypoxic gene set ( Supplementary Fig.1 ).…”

Section: Discussionmentioning

confidence: 97%

“…HBV was purified from a HepAD38 producer line as previously reported 57 . Briefly, virus was purified using centrifugal filter devices (Centricon Plus-70 and Biomax 100.000, Millipore Corp., Bedford, MA) and stocks with a titre between 3×10 9 and 3×10 10 viral genome equivalents (vge) per mL stored at −80°C. HBV-X-virus was purified from a HepG2 based cell line containing a HBV 1.3x overlength integrated viral genome where both 5’ and 3’ HBx genes were knocked out by a point mutation that changes the eight amino acid to a stop codon (CAA-to-TAA) as previously described 44 .…”

Section: Methodsmentioning

confidence: 99%

Hypoxic gene expression in chronic hepatitis B infected patients is not observed in state-of-artin vitroand mouse infection models

Liu

Harris

Marchi

et al. 2020

Preprint

View full text Add to dashboard Cite

25Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. The prolyl hydroxylase 26 domain (PHD)-hypoxia inducible factor (HIF) pathway is a key mammalian oxygen sensing pathway and is frequently 27 perturbed by pathological states including infection and inflammation. We discovered a significant upregulation of 28 hypoxia regulated gene transcripts in patients with chronic hepatitis B (CHB) in the absence of liver cirrhosis. We used 29 state-of-the-art in vitro and in vivo HBV infection models to evaluate a role for HBV infection and the viral regulatory 30 protein HBx to drive HIF-signalling. HBx had no significant impact on HIF expression or associated transcriptional 31 activity under normoxic or hypoxic conditions. Furthermore, we found no evidence of hypoxia gene expression in HBV 32 de novo infection, HBV infected human liver chimeric mice or transgenic mice with integrated HBV genome. 33 Collectively, our data show clear evidence of hypoxia gene induction in CHB that is not recapitulated in existing models 34 for acute HBV infection, suggesting a role for inflammatory mediators in promoting hypoxia gene expression. 35 36 12 13 Although liver cirrhosis is a major risk factor for developing HCC, however, 10-20% of HBV infected patients that 14 develop HCC are non-cirrhotic, highlighting a role for HBV to promote carcinogenesis via direct and indirect 15 inflammatory mechanisms 7 . Three major and non-exclusive viral-dependent pathways have been proposed: (i) 16 integration of viral DNA into the host genome; (ii) expression of viral oncogenic proteins and (iii) viral-driven changes 17 in host gene transcription (reviewed in 8 ). The viral encoded regulatory hepatitis B X protein (HBx) has been reported 18to promote the expression of both viral and selected host genes, where a recent study reported HBx binding to >5,000 19 host genes with diverse roles in metabolism, chromatin maintenance and carcinogenesis 9 . There is clearly an urgent 20 need to increase our understanding of HBV mediated carcinogenesis to support the development of tools to identify 21 CHB patients at risk of HCC development. confirming increased expression of hypoxic genes in CHB liver (Fig.1b). To evaluate other enriched pathways in CHB 1 liver, GSEA was carried out using the Hallmark gene sets from MSigDB. This data base is curated to have minimal 2 overlap between categories, reducing noise and redundancy and summarize specific cell states or biological 3 processes. This analysis identified genes associated with allograft rejection as the most significantly upregulated gene 4 set in CHB. Interestingly HIF-1α was one of the leading-edge genes in this subset; contributing significantly to the core 5 enrichment score. Moreover, we noted a significant increase in inflammatory signaling pathways in CHB liver: 'TNFA 6 signaling via NF-kB', 'Inflammatory Response' and 'Interferon Gamma Response' (Fig.1c). In summary, these data 7 show increased hypoxic gene signatures in CHB liver that associates ...

show abstract

“…Aberrant regulation of miR-15b in human cancers reportedly has an important role in cancer development, contributing to reduced proliferation, cell death, angiogenesis and metabolic reprogramming and metastasis resistance, as well as tumor-associated inflammation and genomic instability (37). miR-576 is directly targeted by hepatitis B virus-encoded X protein (38). miR-155 and miR-500 were reported as potential markers of aflatoxin exposure (39), which suggests that miRs may be used as potential biomarkers for the diagnosis of LTBI.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of microRNA expression between patients with and without latent tuberculosis infections

Wang

Dong

et al. 2019

Exp Ther Med

View full text Add to dashboard Cite

Tuberculosis (TB) is a globally prevalent infectious disease. The mechanisms of latent TB infection (LTBI) remain to be fully elucidated and may provide novel approaches for diagnosis. As therapeutic targets and molecular diagnostic markers, microRNAs (miRs) have been studied and utilized in various diseases. In the present study, the differentially expressed miRs (DEMs) in LTBI were screened and analyzed to determine the underlying mechanisms and identify potential biomarkers, thereby contributing to the diagnosis of LTBI. The GSE25435 and GSE29190 datasets from Gene Expression Omnibus were selected for analysis. The 2 datasets were analyzed individually using the Bioconductor package to screen the DEMs with specific cutoff criteria [P<0.01 and |log (fold change)|≥1]. Target gene prediction and interaction network construction were performed using Targetscan, the Search Tool for the Retrieval of Interacting Genes and Proteins and Cytoscape individually, and were merged using the latter tool. The hub genes were finally selected based on their degree of connectivity (DC). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the KEGG and GENCLIP. A total of 144 DEMs were identified from the 2 datasets. By exploring the overlapping miRs in the two datasets, Homo sapiens (hsa)-miR-29a and hsa-miR-15b were identified to be decreased, while hsa-miR-576-5p, hsa-miR-500 and hsa-miR-155 were identified to be upregulated. hsa-miR-500a-3p and hsa-miR-29a-3p, as well as 4 genes, namely cell division cycle (CDC)42, actin α1, skeletal muscle (ACTA1), phosphatase and tensin homolog (PTEN) and fos proto-oncogene (FOS), were selected as the key factors in this regulatory network. A total of 9 signaling pathways, including phosphoinositide-3 kinase (PI3K)/AKT and 11 biological processes, were identified to be associated with LTBI. In conclusion, the present analysis identified hsa-miR-500a-3p and hsa-miR-29a-3p, as well as CDC42, ACTA1, PTEN and FOS, as the most promising biomarkers and therapeutic candidates for LTBI. The PI3K/AKT signaling pathway is the key signaling pathway implicated in LTBI, and an in-depth investigation of the efficiency of PI3K/AKT signaling inhibitors may be used to prevent a chronic state of infection in LTBI.

show abstract

Genome-wide identification of direct HBx genomic targets

Cited by 57 publications

References 61 publications

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

Hypoxic gene expression in chronic hepatitis B infected patients is not observed in state-of-artin vitroand mouse infection models

Bioinformatics analysis of microRNA expression between patients with and without latent tuberculosis infections

Contact Info

Product

Resources

About