Tet-mediated Epigenetic Modulation in Autism

描述(由申请人提供)：自闭症是由一组临床上不同种类的障碍组成的，统称为自闭症谱系障碍(ASD)，它们具有社会关系受损、语言和沟通障碍以及兴趣和行为范围有限的共同特征。虽然单基因疾病总共只占自闭症病例的一小部分(10%-15%)，但这些疾病中的分子变化可以揭示ASD共有的共同致病途径。胞嘧啶甲基化通过改变DNA-蛋白质相互作用来影响转录状态和细胞特性，从而成为一个关键的表观遗传标记。5-甲基胞嘧啶(5mC)通常被认为是对DNA的一种稳定的共价修饰；然而，5-MC可以被Tet家族蛋白通过Fe(II)α-KG依赖的羟基化而被酶修饰为5-羟甲基胞嘧啶(5hmC)，这一事实为先前观察到的5mC依赖的调控过程的可塑性提供了新的视角。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(CNS)中活性依赖的基因调控和学习记忆。在哺乳动物的大脑中，5mC到5hmC的羟基化呈现了一种特别有趣的表观遗传调节范式，在那里它的动态调节是至关重要的。为了揭示5hmC的生物学，我们开发了绘制全基因组5hmC分布的方法。使用这些技术，我们生成了大脑发育过程中5hmC的全基因组图谱，提供了中枢神经系统中受调控的5hmC的详细表观组学视图。我们的分析表明，在神经发育过程中，5hmC存在高度动态的调节。更具体地说，我们已经确定了神经发育过程中稳定和动态的DHMR(差异5-羟甲基化区)。令人惊讶的是，dhmr高度富含与自闭症有关的基因。我们还发现MeCP2的缺失导致了小脑动态DHMR的5hmC信号的特异性减少。更有趣的是，我们最近发现，导致脆性X综合征的Fmr1的丢失也可能改变小鼠动态Dhmr的5hmC信号。这些数据表明，5hmC介导的表观遗传调节可能广泛影响大脑发育，其调节失调可能导致自闭症。在这项建议中，我们将确定在ASD连锁单基因紊乱的小鼠模型中，动态DHMR上是否存在5hmC修饰的一致性改变，并确定Tet介导的表观遗传调控在ASD连锁单基因紊乱中的功能作用(S)。

DESCRIPTION (provided by applicant): Autism is comprised of a clinically heterogeneous group of disorders, collectively termed "autism spectrum disorders" (ASD), which share common features of impaired social relationship, impaired language and communication, and limited range of interests and behavior. Although monogenic disorders collectively only account for a minority of autism cases (10-15%), the molecular alterations in these disorders could reveal common pathogenic pathways shared by ASDs. 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) alpha-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. To unravel the biology of 5hmC, we have developed approaches to map genome-wide 5hmC distribution. Using these technologies, we generated genome-wide maps of 5hmC during brain development, providing a detailed epigenomic view of regulated 5hmC in CNS. Our analyses suggest a highly dynamic regulation of 5hmC during neurodevelopment. More specifically, we have identified both stable and dynamic DhMRs (Differential 5-hydroxymethylated regions) during neurodevelopment. Surprisingly DhMRs are highly enriched in the genes that have been implicated in autism. We have also found that the loss of Mecp2 leads to the specific reduction of 5hmC signals at dynamic DhMRs of cerebellum. More intriguingly, we have recently found that the loss of Fmr1, responsible for fragile X syndrome, could alter the 5hmC signals at dynamic DhMRs in mice as well. These data suggest that 5hmC-mediated epigenetic regulation may broadly impact brain development, and its dysregulation could contribute to autism. In this proposal, we will determine whether there is consistent alteration of 5hmC modification at dynamic DhMRs among mouse models of ASD-linked monogenic disorders, and determine the functional role(s) of Tet-mediated epigenetic modulation in ASD-linked monogenic disorders.