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

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' 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

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（m6 A）是真核生物中最普遍的、可逆的RNA修饰， 特别是在大脑中。通过m6 A RNA相互作用蛋白的特异性结合， 标记在RNA的多个步骤中对基因表达的转录后调节起重要作用 代谢，包括剪接、输出、降解和翻译。重要的是，神经m6 A中的扰动 m6 A RNA生物学相关因子的景观和异常表达与衰老有关， 神经发育和神经损伤。 最近，已经表明RNA-DNA杂合体或所谓的R环内的RNA可以被m6 A修饰， 这种表观转录组修饰调节了R环的稳定性。R环是三链核酸 由RNA-DNA杂交体和在转录过程中形成的错位ssDNA组成的结构。虽然 R环最初被认为是非常罕见的，但作为正常转录过程的一部分，它可以大量形成。而 短暂的R环形成是正常基因表达的一部分，持久的R环可以阻断正常基因表达。 延长RNA聚合酶，可能导致聚合酶停滞，这既减少基因表达， 促进DNA损伤。值得注意的是，R环稳态的失调与衰老和人类疾病有关。 病理学包括神经变性。这项提议的重点是一种新的可能性， 作为m6 A RNA修饰稳态失调的结果，R环的形成易使衰老 大脑基因表达失衡，导致功能丧失，最终导致神经退行性变。