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Role of m6A RNA modifications in AHR-mediated developmental toxicity

m6A RNA 修饰在 AHR 介导的发育毒性中的作用

基本信息

批准号：
10647294
负责人：
NEELAKANTESWAR Aluru
金额：
$ 45.48万
依托单位：
WOODS HOLE OCEANOGRAPHIC INSTITUTION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-10 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647294
关键词：
3&apos Untranslated Regions Address Adult Affect Agonist Alternative Splicing Aryl Hydrocarbon Receptor Basic Science Cell physiology Central Nervous System Chemical Exposure Chemicals Consensus Sequence DNA Dependence Development Developmental Process Dioxins Disease Dose Embryo Embryonic Development Environment Environmental Exposure Environmental Pollutants Epigenetic Process Exons Exposure to Future Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Genotype Goals Health Immunoprecipitation Individual Life Ligands Link Malignant Neoplasms Measures Mediating Messenger RNA Metabolism Methylation Modification Molecular Nervous System Physiology Nucleotides Pathway interactions Pattern Phenotype Physiological Processes Play Protein Methylation RNA RNA Splicing RNA methylation Reader Regulation Research Resolution Role Site Specificity Stimulus Strategic Planning Terminator Codon Testing Tetrachlorodibenzodioxin Toxic effect Transcript Untranslated RNA Vertebrates Zebrafish aryl hydrocarbon receptor ligand circadian pacemaker crosslink developmental toxicity diphenyl environmental chemical environmental chemical exposure epigenetic regulation epigenomics epitranscriptome epitranscriptomics genome-wide in vivo Model loss of function methylation pattern mutant response screening stressor toxicant transcriptome sequencing vertebrate embryos zebrafish development

项目摘要

Project Summary The overall objective of this R21 proposal is to determine the extent to which environmental chemical exposures affect the most abundant epitranscriptomic mark, N6-methyl-adenosine (m6A) in developing vertebrate embryos. RNA, like DNA, undergo reversible chemical modifications that can potentially influence gene expression. Research so far indicates that m6A modification in mRNAs and ncRNAs plays a critical role in a number of physiological processes including embryonic development, metabolism, central nervous system function and circadian clock regulation. Altered m6A modification has also been linked to a number of disease states including cancer. As many environmental contaminants alter gene expression profiles and have detrimental effects on physiological processes, it is important to understand the effects of exposure on this important layer of gene regulation. Our preliminary results demonstrated that exposure to a dioxin-like polychlorinated biphenyl (PCB) and an aryl hydrocarbon receptor (AHR) during development alter m6A patterns in zebrafish. The proposed research has two specific aims. Aim 1 tests the hypothesis that a diverse group of AHR agonists will alter m6A RNA methylation patterns in a unique set of transcripts. Using three different environmentally relevant dioxin-like PCBs (AHR agonists), we will measure the dose-dependence and ligand-specificity of AHR's role in mediating developmental toxicity and altered m6A RNA methylation patterns. Zebrafish embryos will be exposed to toxicants to evaluate the m6A patterns using m6A individual-nucleotide-resolution cross-linking and immunoprecipitation (mi-CLIP). Using paired-end sequencing of RNA (RNAseq), we will determine the impact of altered m6A methylation on gene expression and mRNA splicing. In Aim 2, we will test the hypothesis that one or more of the players in m6A RNA methylation (m6A writer (mettl3), eraser (fto) and reader (ythdf2)) will have altered sensitivity to AHR agonists. We will expose zebrafish embryos from heterozgyous mutant crosses to different concentrations of an AHR agonist, and compare the sensitivity in responses between genotypes. The proposed research will establish the effects of diverse AHR ligands on m6A RNA methylation patterns, elucidate the impact of altered m6A methylation on gene expression and alternative (mRNA) splicing, and characterize the role of key RNA methylation proteins in toxicant- induced alteration of m6A patterns and gene regulation. These results will form the basis for future studies determining the potential roles of RNA methylation in developmental toxicity as well as developmental basis of adult health and disease.

项目总结