Dynamic DNA Modifications in Brain and Diseases

表观遗传学被广泛定义为基因表达和功能的可遗传变化， 不改变DNA序列。作为DNA序列之间的中间调节范式， 基因表达，表观遗传机制可以对大脑发育产生实质性影响 我们才刚刚开始意识到这一点越来越多的证据表明， 多种神经发育、神经退行性和精神疾病是由 至少部分是由异常的表观遗传修饰造成的。胞嘧啶甲基化是一个关键的 表观遗传标记通过修饰影响转录状态的DNA-蛋白质相互作用， 细胞身份5-甲基胞嘧啶（5 mC）通常被认为是一种稳定的共价键， 然而，5-mC可以被酶促修饰为5-mC的事实是， 泰特家族蛋白通过Fe（II）α-KG依赖性 羟基化为先前观察到的5 mC依赖性的可塑性提供了新的视角。 监管程序。DNA甲基化相关调控过程的表观遗传可塑性 影响中枢神经系统中的活性依赖性基因调节以及学习和记忆 系统（CNS）。5 mC到5 hmC的羟基化呈现了一种特别有趣的表观遗传 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- 甲基腺嘌呤（N6 mA）。因此，在哺乳动物中发现了5 hmC/5 fC/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， 修饰在大脑中丰富。这里的拟议工程将整合各种学科 （遗传学/基因组学，生物信息学，生物化学和细胞生物学）来理解串扰 在神经发育和衰老过程中的动态DNA修饰，以及它们在 神经系统疾病的发病机制

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.