Tet-mediated Epigenetic Modulation in Autism

描述（由申请人提供）：自闭症是由一组临床异质性疾病组成的，统称为“自闭症谱系障碍”（ASD），这些疾病具有社会关系受损、语言和沟通受损以及兴趣和行为范围有限的共同特征。虽然单基因疾病仅占自闭症病例的少数（10-15%），但这些疾病的分子改变可能揭示ASD共有的共同致病途径。胞嘧啶甲基化通过修饰影响转录状态和细胞身份的DNA-蛋白质相互作用作为关键的表观遗传标记。5-甲基胞嘧啶（5 mC）通常被视为对DNA的稳定共价修饰;然而，5-mC可以被泰特家族蛋白通过Fe（II）α-KG依赖性羟基化酶促修饰为5-羟甲基胞嘧啶（5 hmC）的事实为先前观察到的5 mC依赖性调节过程中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）中的活性依赖性基因调控和学习记忆。5 mC到5 hmC的羟基化在哺乳动物大脑中呈现出特别有趣的表观遗传调控范例，其中其动态调控是至关重要的。为了解开5 hmC的生物学，我们已经开发了绘制全基因组5 hmC分布的方法。利用这些技术，我们在大脑发育过程中产生了5 hmC的全基因组图谱，提供了CNS中受调控的5 hmC的详细表观基因组视图。我们的分析表明，在神经发育过程中的5 hmC的高度动态调节。更具体地说，我们已经确定了稳定和动态DhMR（差异5-羟甲基化区域）在神经发育。令人惊讶的是，DhMR高度富集了与自闭症有关的基因。我们还发现，Mecp 2的缺失导致小脑动态DhMR上5 hmC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Fmr 1的缺失也可以改变小鼠动态DhMR中的5 hmC信号。这些数据表明，5 hmC介导的表观遗传调控可能广泛影响大脑发育，其失调可能导致自闭症。在这个提议中，我们将确定在ASD连锁单基因疾病的小鼠模型中，动态DhMR处的5 hmC修饰是否存在一致的改变，并确定Tet-mediated表观遗传调节在ASD连锁单基因疾病中的功能作用。

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.