Insights into Hepatitis B Virus DNA Integration-55 Years after Virus Discovery

Zhao, Kaitao; Liu, Andrew; Xia, Yuchen

doi:10.1016/j.xinn.2020.100034

Cited by 45 publications

(52 citation statements)

References 163 publications

(335 reference statements)

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“…Fibrosis is a pathological characteristic of most chronic inflammatory diseases, and many deep learning methods have been developed to study human diseases ( Wynn and Ramalingam, 2012 ; Chen Q. et al, 2019 ; Cheng and Ghany, 2020 ; Feng et al, 2020 ; Lan et al, 2020 ; Zhao et al, 2020 ). In recent years, fibrosis is recognized as a main reason of the occurrence of adverse events in many chronic inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

Identification of Common Genes and Pathways in Eight Fibrosis Diseases

Shi

Dang

et al. 2021

Front. Genet.

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Acute and chronic inflammation often leads to fibrosis, which is also the common and final pathological outcome of chronic inflammatory diseases. To explore the common genes and pathogenic pathways among different fibrotic diseases, we collected all the reported genes of the eight fibrotic diseases: eye fibrosis, heart fibrosis, hepatic fibrosis, intestinal fibrosis, lung fibrosis, pancreas fibrosis, renal fibrosis, and skin fibrosis. We calculated the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment scores of all fibrotic disease genes. Each gene was encoded using KEGG and GO enrichment scores, which reflected how much a gene can affect this function. For each fibrotic disease, by comparing the KEGG and GO enrichment scores between reported disease genes and other genes using the Monte Carlo feature selection (MCFS) method, the key KEGG and GO features were identified. We compared the gene overlaps among eight fibrotic diseases and connective tissue growth factor (CTGF) was finally identified as the common key molecule. The key KEGG and GO features of the eight fibrotic diseases were all screened by MCFS method. Moreover, we interestingly found overlaps of pathways between renal fibrosis and skin fibrosis, such as GO:1901890-positive regulation of cell junction assembly, as well as common regulatory genes, such as CTGF, which is the key molecule regulating fibrogenesis. We hope to offer a new insight into the cellular and molecular mechanisms underlying fibrosis and therefore help leading to the development of new drugs, which specifically delay or even improve the symptoms of fibrosis.

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Section: Discussionmentioning

confidence: 99%

Identification of Common Genes and Pathways in Eight Fibrosis Diseases

Shi

Dang

et al. 2021

Front. Genet.

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“… 8 Indeed, HBV integrations tend to locate at either sites of host genomic instability, 9 , 10 or sites of cellular DNA damage. 11 Meanwhile, the HBV genome does not encode either integrase or other proteins recognizing specific genomic regions for integration, 9 , 12 , 13 and it is unlikely that HBV could deliberately “target” certain genes or regions. By far, only repeat elements or short homologous sequences, mediating the DNA repairing via non-homologous end joining, are the main genomic feature of integration sites.…”

Section: Introductionmentioning

confidence: 99%

“…During HBV replication, the reverse transcription from pregenomic RNA (commonly referred to as pgRNA) to cccDNA or dslDNA uses an 18 nucleotide RNA primer, which is the hydrolysate of pgRNA, to initiate the synthesis of the positive-sense DNA strand. 12 In about 90% of nucleocapsids, the RNA primer translocates to the DR2, leading to the synthesis of relaxed circular DNA; while in the remaining 10%, it binds to the DR1, priming the synthesis of dslDNA as the main source of viral DNA incorporated into the host genome. 12 …”

Section: Introductionmentioning

confidence: 99%

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HBV Integration Induces Complex Interactions between Host and Viral Genomic Functions at the Insertion Site

Zhang

Protzer

et al. 2021

Journal of Clinical and Translational Hepatology

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Hepatitis B virus (HBV), one of the well-known DNA oncogenic viruses, is the leading cause of hepatocellular carcinoma (HCC). In infected hepatocytes, HBV DNA can be integrated into the host genome through an insertional mutagenesis process inducing tumorigenesis. Dissection of the genomic features surrounding integration sites will deepen our understanding of mechanisms underlying integration. Moreover, the quantity and biological activity of integration sites may reflect the DNA damage within affected cells or the potential survival benefits they may confer. The well-known human genomic features include repeat elements, particular regions (such as telomeres), and frequently interrupted genes (e.g., telomerase reverse transcriptase [i.e. TERT ], lysine methyltransferase 2B [i.e. KMT2B ], cyclin E1 [ CCNE1 ], and cyclin A2 [ CCNA2 ]). Consequently, distinct genomic features within diverse integrations differentiate their biological functions. Meanwhile, accumulating evidence has shown that viral proteins produced by integrants may cause cell damage even after the suppression of HBV replication. The integration-derived gene products can also serve as tumor markers, promoting the development of novel therapeutic strategies for HCC. Viral integrants can be single copy or multiple copies of different fragments with complicated rearrangement, which warrants elucidation of the whole viral integrant arrangement in future studies. All of these considerations underlie an urgent need to develop novel methodology and technology for sequence characterization and function evaluation of integration events in chronic hepatitis B-associated disease progression by monitoring both host genomic features and viral integrants. This endeavor may also serve as a promising solution for evaluating the risk of tumorigenesis and as a companion diagnostic for designing therapeutic strategies targeting integration-related disease complications.

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“…Integration events are known to cause insertional mutagenesis, chromosomal instability, activation of oncogenes, and inflammation, and thus can play a critical role in liver disease progression and the development of hepatocellular carcinoma (HCC) (4).…”

Section: Introductionmentioning

confidence: 99%

Detection of hepatitis B virus-host junction sequences in urine of infected patients

Lin

Trauger

et al. 2021

Preprint

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Background & Aims: Integrated hepatitis B virus (HBV) DNA, found in >85% of HBV-associated hepatocellular carcinomas (HBV-HCC), can play a significant role in HBV-related liver disease progression. HBV-host junction sequences (HBV-JS's), created through integration events, have been used to determine HBV-HCC clonality. Here, we investigate the feasibility of analyzing HBV integration in a noninvasive urine liquid biopsy. Approach & Results: Utilizing an HBV-targeted NGS assay, we first identified HBV-JS's in 8 HBV-HCC tissues and designed short-amplicon junction-specific PCR assays to detect HBV-JSs in matched urine. We detected and validated tissue-derived junctions in 5 of 8 matched urine samples. Next, we screened 32 urine samples collected from 25 HBV-infected patients (5 with hepatitis, 10 with cirrhosis, 4 with HCC, and 6 post-HCC). Encouragingly, all 32 urine samples contained HBV-JS's detectable by HBV-targeted NGS. Of the 712 total HBV-JS's detected in urine, 351 were in gene-coding regions, 11 of which, including TERT, had previously been reported as recurrent integration sites in HCC tissue and were found in urine of cirrhosis or HCC patients only. The integration breakpoints of HBV DNA detected in urine were found predominantly (~70%) at a previously identified integration hotspot, HBV DR1-2. Conclusions: HBV viral-host junction DNA can be detected in urine of HBV-infected patients. This study is the first study to demonstrate the potential for a noninvasive urine liquid biopsy of integrated HBV DNA to monitor HBV-infected patients for HBV-associated liver diseases and the efficacy of antiviral therapy.

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Insights into Hepatitis B Virus DNA Integration-55 Years after Virus Discovery

Cited by 45 publications

References 163 publications

Identification of Common Genes and Pathways in Eight Fibrosis Diseases

Identification of Common Genes and Pathways in Eight Fibrosis Diseases

HBV Integration Induces Complex Interactions between Host and Viral Genomic Functions at the Insertion Site

Detection of hepatitis B virus-host junction sequences in urine of infected patients

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