ViMIC: a database of human disease-related virus mutations, integration sites and cis-effects

Abstract Molecular mechanisms of virus-related diseases involve multiple factors, including viral mutation accumulation and integration of a viral genome into the host DNA. With increasing attention being paid to virus-mediated pathogenesis and the development of many useful technologies to identify virus mutations (VMs) and viral integration sites (VISs), much research on these topics is available in PubMed. However, knowledge of VMs and VISs is widely scattered in numerous published papers which lack standardization, integration and curation. To address these challenges, we built a pilot database of human disease-related Virus Mutations, Integration sites and Cis-effects (ViMIC), which specializes in three features: virus mutation sites, viral integration sites and target genes. In total, the ViMIC provides information on 31 712 VMs entries, 105 624 VISs, 16 310 viral target genes and 1 110 015 virus sequences of eight viruses in 77 human diseases obtained from the public domain. Furthermore, in ViMIC users are allowed to explore the cis-effects of virus-host interactions by surveying 78 histone modifications, binding of 1358 transcription regulators and chromatin accessibility on these VISs. We believe ViMIC will become a valuable resource for the virus research community. The database is available at http://bmtongji.cn/ViMIC/index.php.

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ViMIC: A Database of Human Disease-related Virus Mutations, Integration Sites and Cis-effects

10.1101/2020.10.28.359919 ◽

2020 ◽

Author(s):

Ying Wang ◽

Yuantao Tong ◽

Zeyu Zhang ◽

Rongbin Zheng ◽

Danqi Huang ◽

...

Keyword(s):

Human Disease ◽

Viral Genome ◽

Molecular Mechanisms ◽

Target Genes ◽

Chromatin Accessibility ◽

Viral Integration ◽

Host Interactions ◽

Integration Sites ◽

Transcription Regulators ◽

Virus Research

ABSTRACTMolecular mechanisms of virus-related diseases involve multiple factors, including viral mutation accumulation and integration of a viral genome into the host DNA. With increasing attention being paid to virus-mediated pathogenesis and the development of many useful technologies to identify virus mutations (VMs) and viral integration sites (VISs), abundant literatures on these topics are available in PubMed. However, knowledge of VMs and VISs is widely scattered in numerous published papers, and the association of VMs with VISs in the viral genome or the functional annotation of VISs still lacks integration and curation. To address these challenges, we built a database of human disease-related Virus Mutations, Integration sites and Cis-effects (ViMIC), which specialize in three features: virus mutation sites, viral integration sites and target genes. In total, the ViMIC provides information on 6,461 VMs, 79,089 VISs, and 15,056 viral target genes of 8 viruses in 65 human diseases obtained from literatures. Furthermore, in ViMIC, users are allowed to explore the cis-effects of virus-host interactions by surveying 78 histone modifications, binding of 1,358 transcription regulators, and chromatin accessibility on these VISs. We believe ViMIC will become a valuable resource for the virus research community. The database is available at http://bmtongji.cn/ViMIC/index.php.

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VISDB: a manually curated database of viral integration sites in the human genome

Nucleic Acids Research ◽

10.1093/nar/gkz867 ◽

2019 ◽

Vol 48 (D1) ◽

pp. D633-D641 ◽

Cited By ~ 6

Author(s):

Deyou Tang ◽

Bingrui Li ◽

Tianyi Xu ◽

Ruifeng Hu ◽

Daqiang Tan ◽

...

Keyword(s):

Human Genome ◽

Motif Discovery ◽

Target Genes ◽

Integration Site ◽

Cpg Islands ◽

Fragile Sites ◽

Viral Integration ◽

Sequence Motif ◽

Host Interactions ◽

Integration Sites

Abstract Virus integration into the human genome occurs frequently and represents a key driving event in human disease. Many studies have reported viral integration sites (VISs) proximal to structural or functional regions of the human genome. Here, we systematically collected and manually curated all VISs reported in the literature and publicly available data resources to construct the Viral Integration Site DataBase (VISDB, https://bioinfo.uth.edu/VISDB). Genomic information including target genes, nearby genes, nearest transcription start site, chromosome fragile sites, CpG islands, viral sequences and target sequences were integrated to annotate VISs. We further curated VIS-involved oncogenes and tumor suppressor genes, virus–host interactions involved in non-coding RNA (ncRNA), target gene and microRNA expression in five cancers, among others. Moreover, we developed tools to visualize single integration events, VIS clusters, DNA elements proximal to VISs and virus–host interactions involved in ncRNA. The current version of VISDB contains a total of 77 632 integration sites of five DNA viruses and four RNA retroviruses. VISDB is currently the only active comprehensive VIS database, which provides broad usability for the study of disease, virus related pathophysiology, virus biology, host–pathogen interactions, sequence motif discovery and pattern recognition, molecular evolution and adaption, among others.

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Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

10.1101/2020.02.10.941872 ◽

2020 ◽

Author(s):

Connor Rogerson ◽

Samuel Ogden ◽

Edward Britton ◽

Yeng Ang ◽

Andrew D. Sharrocks ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Molecular Mechanisms ◽

Target Genes ◽

Prognostic Significance ◽

Gene Expression Signature ◽

Chromatin Accessibility ◽

Oesophageal Adenocarcinoma ◽

Cell Cycle Gene ◽

A Cell

AbstractOesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths and yet compared to other common cancers, we know relatively little about the underlying molecular mechanisms. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the specific events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies of BO and OAC and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin in OAC cells to directly regulate cell cycle genes specifically in OAC. Our findings have potential prognostic significance as the survival of patients with high expression of KLF5 target genes is significantly lower. We have provided new insights into the gene expression networks in OAC and the mechanisms behind progression to OAC, chiefly the repurposing of KLF5 for novel regulatory activity in OAC.

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Dr.VIS: a database of human disease-related viral integration sites

Nucleic Acids Research ◽

10.1093/nar/gkr1142 ◽

2011 ◽

Vol 40 (D1) ◽

pp. D1041-D1046 ◽

Cited By ~ 11

Author(s):

X. Zhao ◽

Q. Liu ◽

Q. Cai ◽

Y. Li ◽

C. Xu ◽

...

Keyword(s):

Human Disease ◽

Viral Integration ◽

Integration Sites

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Viral integration transforms chromatin to drive oncogenesis

10.1101/2020.02.12.942755 ◽

2020 ◽

Cited By ~ 1

Author(s):

Mehran Karimzadeh ◽

Christopher Arlidge ◽

Ariana Rostami ◽

Mathieu Lupien ◽

Scott V. Bratman ◽

...

Keyword(s):

Integration Site ◽

Chromatin Accessibility ◽

The Cancer Genome Atlas ◽

Ctcf Binding ◽

Ctcf Binding Site ◽

Viral Integration ◽

Sequence Motif ◽

Integration Sites ◽

Almost All ◽

Upregulated Genes

AbstractHuman papillomavirus (HPV) drives almost all cervical cancers and up to ∼70% of head and neck cancers. Frequent integration into the host genome occurs only for tumourigenic strains of HPV. We hypothesized that changes in the epigenome and transcriptome contribute to the tumourigenicity of HPV. We found that viral integration events often occurred along with changes in chromatin state and expression of genes near the integration site. We investigated whether introduction of new transcription factor binding sites due to HPV integration could invoke these changes. Some regions within the HPV genome, particularly the position of a conserved CTCF sequence motif, showed enriched chromatin accessibility signal. ChIP-seq revealed that the conserved CTCF sequence motif within the HPV genome bound CTCF in 5 HPV+ cancer cell lines. Significant changes in CTCF binding pattern and increases in chromatin accessibility occurred exclusively within 100 kbp of HPV integration sites. The chromatin changes co-occurred with out-sized changes in transcription and alternative splicing of local genes. We analyzed the essentiality of genes upregulated around HPV integration sites of The Cancer Genome Atlas (TCGA) HPV+ tumours. HPV integration upregulated genes which had significantly higher essentiality scores compared to randomly selected upregulated genes from the same tumours. Our results suggest that introduction of a new CTCF binding site due to HPV integration reorganizes chromatin and upregulates genes essential for tumour viability in some HPV+ tumours. These findings emphasize a newly recognized role of HPV integration in oncogenesis.

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Dme-Hsa Disease Database (DHDD): Conserved Human Disease-Related miRNA and Their Targeting Genes in Drosophila melanogaster

International Journal of Molecular Sciences ◽

10.3390/ijms19092642 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2642 ◽

Cited By ~ 2

Author(s):

Guanyun Wei ◽

Lianjie Sun ◽

Shijie Qin ◽

Ruimin Li ◽

Liming Chen ◽

...

Keyword(s):

Drosophila Melanogaster ◽

Human Disease ◽

Molecular Mechanisms ◽

Target Genes ◽

Target Prediction ◽

Human Diseases ◽

Ideal Model ◽

Comprehensive Collection ◽

Disease Related Genes ◽

Visual Network

Abnormal expressions of microRNA (miRNA) can result in human diseases such as cancer and neurodegenerative diseases. MiRNA mainly exert their biological functions via repressing the expression of their target genes. Drosophila melanogaster (D. melanogaster) is an ideal model for studying the molecular mechanisms behind biological phenotypes, including human diseases. In this study, we collected human and D. melanogaster miRNA as well as known human disease-related genes. In total, we identified 136 human disease-related miRNA that are orthologous to 83 D. melanogaster miRNA by mapping “seed sequence”, and 677 human disease-related genes that are orthologous to 734 D. melanogaster genes using the DRSC Integrative Ortholog Prediction Tool Furthermore, we revealed the target relationship between genes and miRNA using miRTarBase database and target prediction software, including miRanda and TargetScan. In addition, we visualized interaction networks and signalling pathways for these filtered miRNA and target genes. Finally, we compiled all the above data and information to generate a database designated DHDD This is the first comprehensive collection of human disease-related miRNA and their targeting genes conserved in a D. melanogaster database. The DHDD provides a resource for easily searching human disease-related miRNA and their disease-related target genes as well as their orthologs in D. melanogaster, and conveniently identifying the regulatory relationships among them in the form of a visual network.

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Chromatin accessibility combined with enhancer clusters activation mediates heterogeneous response to dexamethasone in myeloma cells

10.1101/2021.09.06.459068 ◽

2021 ◽

Author(s):

Victor GABORIT ◽

Jonathan CRUARD ◽

Catherine Guerin-Charbonnel ◽

Jennifer Derrien ◽

Jean-Baptiste Alberge ◽

...

Keyword(s):

Molecular Mechanisms ◽

Target Genes ◽

Interaction Network ◽

Chromatin Accessibility ◽

Enhancer Activity ◽

Myeloma Cells ◽

Combinatorial Assembly ◽

Induced Apoptosis ◽

Combination Regimens

Glucocorticoids (GC) effects occur through binding to the GC receptor (GR) which, once translocated to the nucleus, binds to GC response elements (GREs) to activate or repress target genes. Among GCs, dexamethasone (Dex) is widely used in treatment of multiple myeloma (MM), mainly in combination regimens. However, despite a definite benefit, all patients relapse. Moreover, while GC efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive. To determine the functional role of GR binding in myeloma cells, we generated bulk and single cell multi-omic data and high-resolution contact maps of active enhancers and target genes. We show that a minority (6%) of GR binding sites are associated with enhancer activity gains and increased interaction loops. We find that enhancers contribute to regulate gene activity through combinatorial assembly of large stretches of enhancers and/or enhancer cliques. Furthermore, one enhancer, proximal to GR-responsive genes, is predominantly associated with increased chromatin accessibility and higher H3K27ac occupancy. Finally, we show that Dex exposure leads to co-accessibility changes between predominant enhancer and other regulatory regions of the interaction network. Notably, these epigenomic changes are associated with cell-to-cell transcriptional heterogeneity. As consequences, BIM critical for GR-induced apoptosis and CXCR4 protective from chemotherapy-induced apoptosis are rather upregulated in different cells. In summary, our work provides new insights into the molecular mechanisms involved in Dex escape.

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Dr.VIS v2.0: an updated database of human disease-related viral integration sites in the era of high-throughput deep sequencing

Nucleic Acids Research ◽

10.1093/nar/gku1074 ◽

2014 ◽

Vol 43 (D1) ◽

pp. D887-D892 ◽

Cited By ~ 10

Author(s):

Xiaobo Yang ◽

Ming Li ◽

Qi Liu ◽

Yabing Zhang ◽

Junyan Qian ◽

...

Keyword(s):

High Throughput ◽

Deep Sequencing ◽

Human Disease ◽

Viral Integration ◽

Integration Sites

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Identification of virulence associated milRNAs and their bidirectional targets in Rhizoctonia solani and maize during infection

BMC Plant Biology ◽

10.1186/s12870-021-02930-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hongxu Meng ◽

Shaoli Wang ◽

Wei Yang ◽

Xinhua Ding ◽

Ning Li ◽

...

Keyword(s):

Rhizoctonia Solani ◽

Molecular Mechanisms ◽

Target Genes ◽

Expression Patterns ◽

Anastomosis Group ◽

Luciferase Assay ◽

Comprehensive Overview ◽

Positive Role ◽

Host Interactions ◽

Pathogenesis Related

Abstract Background Anastomosis group 1 IA (AG1-IA) of Rhizoctonia solani is the major agent of banded leaf and sheath blight (BLSB) disease that causes severe yield loss in many worldwide crops. MicroRNAs (miRNAs) are ~ 22 nt non-coding RNAs that negatively regulate gene expression levels by mRNA degradation or translation inhibition. A better understanding of miRNA function during AG1-IA infection can expedite to elucidate the molecular mechanisms of fungi-host interactions. Results In this study, we sequenced three small RNA libraries obtained from the mycelium of AG1-IA isolate, non-infected maize sheath and mixed maize sheath 3 days after inoculation. In total, 137 conserved and 34 novel microRNA-like small RNAs (milRNAs) were identified from the pathogen. Among these, one novel and 17 conserved milRNAs were identified as potential virulence-associated (VA) milRNAs. Subsequently, the prediction of target genes for these milRNAs was performed in both AG1-IA and maize, while functional annotation of these targets suggested a link to pathogenesis-related biological processes. Further, expression patterns of these virulence-associated milRNAs demonstrated that theyparticipate in the virulence of AG1-IA. Finally, regulation of one maize targeting gene, GRMZM2G412674 for Rhi-milRNA-9829-5p, was validated by dual-luciferase assay and identified to play a positive role in BLSB resistance in two maize mutants. These results suggest the global differentially expressed milRNAs of R. solani AG1-IA that participate in the regulation of target genes in both AG1-IA and maize to reinforce its pathogenicity. Conclusions Our data have provided a comprehensive overview of the VA-milRNAs of R. solani and identified that they are probably the virulence factors by directly interfered in host targeting genes. These results offer new insights on the molecular mechanisms of R.solani-maize interactions during the process of infection.

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The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury

Journal of the American Society of Nephrology ◽

10.1681/asn.2019050534 ◽

2020 ◽

Vol 31 (4) ◽

pp. 716-730 ◽

Cited By ~ 1

Author(s):

Marc Johnsen ◽

Torsten Kubacki ◽

Assa Yeroslaviz ◽

Martin Richard Späth ◽

Jannis Mörsdorf ◽

...

Keyword(s):

Gene Expression ◽

Reperfusion Injury ◽

Caloric Restriction ◽

Molecular Mechanisms ◽

Target Genes ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Hypoxic Preconditioning ◽

Preventive Strategies ◽

Gene Expression Signatures

BackgroundAlthough AKI lacks effective therapeutic approaches, preventive strategies using preconditioning protocols, including caloric restriction and hypoxic preconditioning, have been shown to prevent injury in animal models. A better understanding of the molecular mechanisms that underlie the enhanced resistance to AKI conferred by such approaches is needed to facilitate clinical use. We hypothesized that these preconditioning strategies use similar pathways to augment cellular stress resistance.MethodsTo identify genes and pathways shared by caloric restriction and hypoxic preconditioning, we used RNA-sequencing transcriptome profiling to compare the transcriptional response with both modes of preconditioning in mice before and after renal ischemia-reperfusion injury.ResultsThe gene expression signatures induced by both preconditioning strategies involve distinct common genes and pathways that overlap significantly with the transcriptional changes observed after ischemia-reperfusion injury. These changes primarily affect oxidation-reduction processes and have a major effect on mitochondrial processes. We found that 16 of the genes differentially regulated by both modes of preconditioning were strongly correlated with clinical outcome; most of these genes had not previously been directly linked to AKI.ConclusionsThis comparative analysis of the gene expression signatures in preconditioning strategies shows overlapping patterns in caloric restriction and hypoxic preconditioning, pointing toward common molecular mechanisms. Our analysis identified a limited set of target genes not previously known to be associated with AKI; further study of their potential to provide the basis for novel preventive strategies is warranted. To allow for optimal interactive usability of the data by the kidney research community, we provide an online interface for user-defined interrogation of the gene expression datasets (http://shiny.cecad.uni-koeln.de:3838/IRaP/).

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