Epitranscriptomics of the aging lung

摘要 肺系统的正常老化与多种生理、解剖和分子机制有关， 肺部的变化。表观遗传标记，人类基因组中基于非序列的变异，已经被 被认为是正常衰老的重要分子标志，研究主要集中在DNA，而不是RNA， 甲基化表位转录组学是指RNA修饰的研究。N6-甲基腺苷（m6 A）是最多的 研究了这些RNA修饰，但肺组织中与衰老相关的整体RNA甲基化尚未被发现。 探讨了我们推测肺组织中差异RNA甲基化可能代表了一个新的研究方向 促进对正常肺生物学和基因组学随衰老变化的理解。鉴于越来越 证据表明，正常老化具有累积的分子影响，考虑到年龄相关的变化， epitranscriptome可以推进对肺中与年龄相关的弹性的了解。我们将研究全球RNA 1）定量肺组织中的总体N6-甲基-腺苷 来自肺组织研究联盟的400名肺功能正常的个体，探索肺功能的变化。 RNA甲基化随年龄的变化，另外考虑性别和种族相关的变异性; 与RNA甲基化相关的遗传变异; 3）评估RNA甲基化作为 基因表达和肺组织中基因调控网络特征的贡献者。当前公开报道中还没有 正常肺中RNA甲基化和衰老的研究。该项目将研究RNA甲基化是否 捕获肺中的正常老化，并将支持对作为标记物的表转录组进行更深入的评估 肺部健康本提案是对PA-19-049（推进NHBLI的新研究方向）的响应 Strategic Vision Normal Biology）通过对肺组织中与衰老相关的RNA非序列变异进行建模 肺功能正常的人。

ABSTRACT Normal aging of the pulmonary system associates with a multitude of physiologic, anatomic and molecular changes in the lung. Epigenetic marks, non-sequence based variations in the human genome, have been identified as important molecular hallmark of normal aging, with investigations mainly focused on DNA, not RNA, methylation. Epitranscriptomics refers to studies of modifications of RNA. N6-methyl-adenosine (m6A) is the most studied of these RNA modifications, but aging-related global RNA methylation in lung tissue has not been explored. We hypothesize that differential RNA methylation in lung tissue may represent a new research direction for advancing understanding of normal lung biology and genomics changes with aging. Given the growing evidence that normal aging has a cumulative molecular impact, considering age-related changes to the epitranscriptome may advance insights into age-related resilience in the lung. We will investigate global RNA methylation through the following Specific Aims : 1) Quantification of global N6-methyl-adenosine in lung tissue from 400 individuals with normal spirometry from the Lung Tissue Research Consortium, exploring variability of RNA methylation with age, with additional consideration of sex and race associated variability; 2) Identification of genetic variation that associates with RNA methylation; 3)Evaluation of RNA methylation as a predictor of gene expression and a contributor to gene regulatory network signatures in lung tissue. There are no published studies of RNA methylation and aging in the normal lung. This project will address whether RNA methylation captures normal aging in the lung and will support more in-depth evaluations of the epitranscriptome as a marker of lung health. This proposal is responsive to PA-19-049 (New Research Directions to Advance the NHBLI Strategic Vision Normal Biology) by modeling aging associated non-sequence variation of RNA in lung tissue from individuals with normal lung function.