Dynamic DNA Modifications in Brain and Diseases

大脑和疾病中的动态 DNA 修饰

• 批准号: 10458715
• 负责人: PENG JIN
• 金额: $ 85.35万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458715
• 关键词: Adenosine; Aging; Biochemistry; Bioinformatics; Brain; Brain Diseases; Cellular biology; Cytosine; DNA; DNA Methylation; DNA Modification Process; DNA Sequence; DNA-Protein Interaction; Development; Discipline; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genetic; Genetic Transcription; Genomics; Heritability; Hydroxylation; Learning; Memory; Mental disorders; Methylation; Modification; Neuraxis; Neurodegenerative Disorders; Neurodevelopmental Disorder; Pathogenesis; Process; Protein Family; Regulation; Role; Tetanus Helper Peptide; Work; gene function; human disease; mammalian genome; nervous system disorder; neurodevelopment; novel

Epigenetics is broadly defined as the heritable changes in gene expression and function that do not alter DNA sequence. As an intermediate regulatory paradigm between DNA sequences and gene expression, epigenetic mechanisms can exert substantial influence on brain development on a scale that we are only beginning to appreciate. Furthermore increasing evidence indicates that multiple neurodevelopmental, neurodegenerative, and psychiatric disorders are caused, at least in part, by aberrant epigenetic modifications. Cytosine methylation serves as a critical epigenetic mark by modifying DNA-protein interactions that influence transcriptional states and cellular identity. 5-methylcytosine (5mC) has generally been viewed as a stable covalent modification to DNA; however, the fact that 5-mC can be enzymatically modified to 5- hydroxymethylcytosine (5hmC) by Tet family proteins through Fe(II) α-KG-dependent hydroxylation gives a new perspective on the previously observed plasticity in 5mC-dependent regulatory processes. Epigenetic plasticity in DNA methylation-related regulatory processes influences activity-dependent gene regulation and learning and memory in the central nervous system (CNS). Hydroxylation of 5mC to 5hmC presents a particularly intriguing epigenetic regulatory paradigm in the mammalian brain, where its dynamic regulation is critical. Emerging evidence also suggests potential epigenetic roles for a novel DNA adenosine modification, N6- methyladenine (N6mA). Thus the discovery of both 5hmC/5fC/5caC and N6mA in mammalian genome significantly increases the DNA epigenetic complexity and intriguingly all these modifications are enriched in brain. The proposed works here will integrate various disciplines (genetics/genomics, bioinformatics, biochemistry, and cell biology) to understand the crosstalk among the dynamic DNA modifications during neurodevelopment and aging, and their roles in the pathogenesis of neurological disorders.

表观遗传学被广泛地定义为基因表达和功能的可遗传变化 而不是改变DNA序列。作为DNA序列和DNA序列之间的中间调控范例 基因表达，表观遗传机制可以对大脑发育产生实质性影响 规模之大，我们才刚刚开始欣赏。此外，越来越多的证据表明 导致多种神经发育、神经退行性和精神障碍，在 至少在一定程度上，是通过异常的表观遗传修饰。胞嘧啶甲基化是一种关键 通过改变DNA-蛋白质相互作用来影响转录状态和表观遗传标记 手机身份。5-甲基胞嘧啶(5mC)通常被认为是一种稳定的共价化合物 DNA的修饰；然而，5-MC可以被酶修饰为5-MC的事实 依赖Fe(II)α-KG的Tet家族蛋白对羟甲基胞嘧啶(5HmC)的作用 羟化为先前观察到的5mC依赖的可塑性提供了新的视角 监管流程。DNA甲基化相关调控过程中的表观遗传可塑性 影响中枢神经系统的活性依赖基因调控和学习记忆 系统(CNS)。5mC到5hmC的羟基化呈现一种特别耐人寻味的表观遗传学 在哺乳动物的大脑中，它的动态调节是至关重要的。新兴 证据还表明，一种新的DNA腺苷修饰N6-可能具有表观遗传学作用。 甲基腺嘌呤(N6 MA)。因此，在哺乳动物中发现了5hmC/5fC/5caC和N6 mA 基因组显著增加了DNA表观遗传的复杂性，有趣的是，所有这些 修饰在大脑中得到丰富。这里拟建的作品将融合多个学科 (遗传学/基因组学、生物信息学、生物化学和细胞生物学)来了解串扰 在神经发育和衰老过程中的动态DNA修饰，以及它们在 神经性疾病的发病机制。