m6A RNA modification as a regulator of R-loop homeostasis and gene expression in aging and neurodegeneration

m6A RNA 修饰作为衰老和神经退行性疾病中 R 环稳态和基因表达的调节剂

基本信息

批准号：
10433143
负责人：
Hana Hall
金额：
$ 37.55万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10433143
关键词：
Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Animal Model Binding Biology Brain DNA DNA Damage DNA-Directed RNA Polymerase Data Deposition Development Disease Drosophila genus Drosophila melanogaster Elderly Eukaryota Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genomics Homeostasis Human Pathology Hybrids Immunoprecipitation Impaired cognition Impairment Incidence Lead Learning Link Memory Memory Loss Methyltransferase Modification Molecular Nerve Degeneration Neurodegenerative Disorders Neurologic Neurons Pathway interactions Phenotype Play Polymerase Population Post-Transcriptional Regulation Process Proteins RNA RNA Processing RNA Splicing RNA Stability RNA metabolism RNA-Binding Proteins Reader Research Risk Factors Role SETX gene Symptoms Testing Transcript Transcription Process Translations age related age related neurodegeneration aging brain cognitive function fly genome-wide helicase insight loss of function neuron loss neuronal survival neurotoxicity novel nucleic acid structure overexpression protein expression relating to nervous system therapeutic development transcriptome sequencing transcriptomics

项目摘要

The N6-methyladenosine (m6A) is the most prevalent, reversible modification of RNA in eukaryotes with high expression specifically in the brain. Through the specific binding of m6A RNA-interacting proteins, this dynamic mark plays an important role in the post-transcriptional regulation of gene expression at many steps of RNA metabolism, including splicing, export, degradation and translation. Importantly, perturbation in the neural m6A landscape and aberrant expression of m6A RNA biology-associated factors is linked with aging, neurodevelopmental and neurological impairments. Recently, it has been shown that RNA within an RNA-DNA hybrid, or so-called R-loop, can be m6A modified and that this epi-transcriptomic modification regulates the stability of R-loops. R-loops are three-stranded nucleic acid structures consisting of an RNA-DNA hybrid and a misplaced ssDNA that form during transcription. Although originally thought to be quite rare, R-loops can form abundantly as part of the normal transcription process. While transient R-loop formation is required as a part of normal gene expression, persistent R-loops can block the elongating RNA polymerase, potentially leading to polymerase stalling, which both reduces gene expression and promotes DNA damage. Notably, dysregulation of R-loop homeostasis has been linked with aging and human pathologies including neurodegeneration. This proposal focuses on a novel possibility that increased persistent R-loop formation, as a consequence of dysregulation of m6A RNA modification homeostasis, predisposes aging brain to imbalance in gene expression leading to loss of function and ultimately, neurodegeneration.

N6-甲基腺苷 (m6A) 是真核生物中最普遍、可逆的 RNA 修饰，具有高特异地在大脑中表达。通过 m6A RNA 相互作用蛋白的特异性结合，这种动态标记在RNA许多步骤的基因表达转录后调控中发挥着重要作用代谢，包括剪接、输出、降解和翻译。重要的是，神经 m6A 的扰动 m6A RNA 生物学相关因子的景观和异常表达与衰老有关，神经发育和神经功能障碍。最近，研究表明，RNA-DNA 杂交体（或所谓的 R 环）中的 RNA 可以进行 m6A 修饰并这种表观转录组修饰调节 R 环的稳定性。 R环是三链核酸由 RNA-DNA 杂交体和转录过程中形成的错位 ssDNA 组成的结构。虽然 R 环最初被认为非常罕见，但作为正常转录过程的一部分，它可以大量形成。尽管短暂的 R 环形成是正常基因表达的一部分，持久的 R 环可以阻断延长 RNA 聚合酶，可能导致聚合酶停滞，这既会降低基因表达，促进DNA损伤。值得注意的是，R 环稳态失调与衰老和人类衰老有关。病理包括神经变性。该提案侧重于一种新的可能性，该可能性增加了持久性 m6A RNA 修饰稳态失调导致 R 环形成，导致衰老大脑基因表达失衡导致功能丧失，最终导致神经退行性变。