Role of neuron-specific nucleosome remodeling in intellectual disability

描述（由申请人提供）：智力障碍以认知、社会行为和沟通障碍为特征。最近的人类外显子组测序研究已经确定了多态BAF复合物（哺乳动物SWI/SNF染色质重塑复合物）的亚基，这些亚基在散发性智力迟钝和散发性自闭症中经常发生突变。此外，神经元特异性brg1相关因子（nBAF）核小体重塑复合体的各种亚基的新生突变与Coffin-Siris综合征和Nicolaides-Baraitser综合征有关，这两种综合征都与智力残疾有关。总之，这些研究表明nBAF功能对于正常的认知功能是必要的。核小体重塑复合物通过在基因启动子处重新定位核小体来修饰染色质结构并调节表达。为什么通过BAF复合物突变干扰染色质重塑导致认知功能障碍尚不清楚。尽管核小体重构在其他领域（如酵母遗传学和癌症）是一个重要的课题，但在神经科学领域却很少受到关注。然而，一个重要的发现是鉴定了第一个神经元特异性BAF复合物，随后发现该复合物调节前体细胞转化为终末分化神经元所需的基因表达。重要的是，nBAF复合物有一个亚基BAF53b，它参与使nBAF神经元特异性。该亚基是神经元和nBAF复合物特异性的，使其成为研究nBAF突触生理和行为的潜在贡献的理想靶标。基于这一点，我们提出验证BAF53b在发育过程中对神经元命运决定发挥关键作用后，继续调节基因表达的假设，并以一种对成人可塑性和记忆至关重要的方式进行。我们提出三个具体目标来检验这一假设。在Aim 1中，我们将使用转基因小鼠来检测BAF53b在长期记忆中的作用。在Aim 2中，我们将研究BAF53b在长期增强中的作用，这是突触可塑性的一种形式。在Aim 3中，我们将使用下一代测序，RNA测序，来确定在记忆巩固过程中哪些基因表达谱是由BAF53b调节的。总之，在这些目标下的工作将阐明BAF53b和nBAF复合物对记忆过程的贡献，从而显著有助于理解该复合物的突变如何导致人类认知障碍。

DESCRIPTION (provided by applicant): Intellectual disorders are characterized by impairments in cognition, social behaviors, and communication. Recent human exome sequencing studies have identified subunits of the polymorphic BAF complexes (mammalian SWI/SNF chromatin remodeling complex) that are frequently mutated in sporadic mental retardation and sporadic autism. Moreover, de novo mutations in various subunits of neuron-specific Brg1-associated factor (nBAF) nucleosome remodeling complex have been implicated in Coffin-Siris and Nicolaides-Baraitser syndromes, both of which are associated with intellectual disability. Together, these studies suggest that nBAF function is necessary for normal cognitive function. Nucleosome remodeling complexes modify chromatin structure and regulate expression by repositioning nucleosomes at the promoters of genes. Why disturbances to chromatin remodeling via mutations in BAF complexes result in cognitive dysfunction is unknown. Although an important topic in other fields (e.g. yeast genetics and cancer), nucleosome remodeling has received little attention in neuroscience. However, a major discovery was the identification of the first neuron-specific BAF complex, which was subsequently found to regulate gene expression required for the conversion of precursor cells into terminally differentiated neurons. Importantly, the nBAF complex has a subunit, BAF53b, which participates in making nBAF neuron- specific. This subunit is both neuron and nBAF complex specific, making it an ideal target for investigating the potential contributions of nBAF t synaptic physiology and behavior. Building on this point, we propose to test the hypothesis that BAF53b, after playing a key role in neuronal fate decisions during development, continues to regulate gene expression and does so in a manner critical to adult plasticity and memory. We propose three specific aims to test this hypothesis. In Aim 1, we will use genetically modified mice to examine the role of BAF53b in long-term memory. In Aim 2, we will examine the role of BAF53b in long-term potentiation, a form of synaptic plasticity. In Aim 3, we will use next generation sequencing, RNA seq, to determine what gene expression profiles are being regulated by BAF53b during memory consolidation. Together, the work under these aims will elucidate the contributions of BAF53b, and the nBAF complex in general, to memory processes, and thereby significantly contribute to the understanding of how mutations in the complex lead to cognitive impairments in humans.