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Epitranscriptomic regulation of HBV gene expression

HBV基因表达的表观转录组调控

基本信息

批准号：
10361391
负责人：
ALEEM SIDDIQUI
金额：
$ 39.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10361391
关键词：
3&apos Untranslated Regions 5&apos Untranslated Regions Adenosine Affinity Antiviral Agents Applications Grants Binding Bioinformatics Biological Assay Biological Process Capsid Cell Nucleus Cells Chronic Chronic Hepatitis Chronic Hepatitis B Circular DNA Code Core Protein DNA DNA biosynthesis Data Development Enzymes Gene Expression Genetic Transcription Genome Genomic DNA Health Hepatitis B Virus Homeostasis Human Immune response Immunoprecipitation Infection Inflammation Length Life Cycle Stages Liver Liver diseases Messenger RNA Methods Methylation Methyltransferase Modification Monitor Mutate Mutation Nucleosome Core Particle Nucleotides Obesity Pathogenesis Patients Play Poly(A)+ RNA Positioning Attribute Primary carcinoma of the liver cells Process Proteins RNA RNA Viruses RNA methylation Regulation Reporting Research Resolution Reverse Transcription Risk Factors Role Scheme Site Stress Structure System Techniques Terminator Codon Tissues Transcript Translations Vaccines Viral Viral Genome Viral Proteins Virus Virus Diseases Virus Replication Withdrawal base design epitranscriptomics liver biopsy therapeutically effective transcriptome viral DNA viral RNA

项目摘要

Project Summary/Abstract Human hepatitis B virus (HBV causes chronic hepatitis. Chronic hepatitis B is a major risk factor in the progression to the onset of hepatocellular carcinoma (HCC). In spite of an effective vaccine and currently used antivirals, there are estimated 350 million infected carriers worldwide. Antivirals do not eliminate HBV DNA in the nucleus. A better understanding of the role of host and viral factors contributing to chronic hepatitis is needed. Epitranscriptomic regulation of HBV gene expression provides another layer of regulatory schemes of gene expression. In this study, we propose to characterize the posttranscriptional modification of viral RNAs at the N6 position of the adenosine base termed m6A. Our extensive preliminary studies described in the grant application show that HBV RNAs are methylated as m6A. Using the strategy of silencing of host methylases and demethylase enzymes involved in epitranscriptomic homeostasis, we present evidence that HBV RNAs are m6A modified. There was clearly an effect on translation of viral transcripts in the absence of enzyme that catalyze m6A modification. Our results with MeRIP immunoprecipitation followed by Tru-seq analysis identified a potential range of sequences enriched in a peak of m6A residues. We mutated about 13 `A' residues in this region that spans from nucleotides 1700 to 2000 within the HBV genome. These were examined for translation of HBV proteins and reverse transcription function. Results were striking, in that, the translation was negatively regulated but reverse transcription was positively regulated by m6A modification. Based on these exciting data, we propose to continue characterization of m6A modification of HBV RNAs and identify the functional relevance of this modification in the HBV infection. This study opens a new avenue of HBV research to investigate epitranscriptomic regulation of the unique HBV life cycle and possible contribution to the progression to chronicity associated with infection.

项目总结/文摘