Role of neuron-specific nucleosome remodeling in intellectual disability

描述(由申请人提供)：智力障碍的特征是认知、社会行为和沟通方面的障碍。最近的人类外显子组测序研究发现，BAF复合体(哺乳动物的SWI/SNF染色质重塑复合体)的亚基在散发性精神发育迟缓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)核小体重塑复合体各亚单位的从头突变与Coffin-Siris和Nicolaides-Baraitser综合征有关，这两种综合征都与智能障碍有关。综上所述，这些研究表明nBAF功能是正常认知功能所必需的。核小体重塑复合体通过将核小体重新定位在基因启动子上来改变染色质结构并调节表达。为什么通过BAF复合体突变对染色质重塑的干扰会导致认知功能障碍尚不清楚。虽然在其他领域(如酵母遗传学和癌症)，核小体重塑是一个重要的话题，但在神经科学中，核小体重塑很少受到关注。然而，一项重大发现是鉴定了第一个神经元特异性的BAF复合体，随后发现它调节前体细胞向终末分化神经元转化所需的基因表达。重要的是，nBAF复合体有一个亚基BAF53b，它参与使nBAF具有神经元特异性。该亚基既是神经元特异性的，也是nBAF复合体特异的，使其成为研究nBAF突触生理和行为潜在贡献的理想靶点。在这一点的基础上，我们建议测试这一假设，即BAF53b在发育过程中在神经元命运决定中发挥关键作用后，继续调节基因表达，并以对成人可塑性和记忆至关重要的方式做到这一点。我们提出了三个具体目标来检验这一假设。在目标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。在目标2中，我们将研究BAF53b在长时程增强中的作用，长时程增强是突触可塑性的一种形式。在目标3中，我们将使用下一代测序，RNA序列，来确定在记忆巩固过程中BAF53b调控哪些基因表达谱。总之，在这些目标下的工作将阐明BAF53b和一般的nBAF复合体对记忆过程的贡献，从而大大有助于理解该复合体的突变是如何导致人类认知障碍的。

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.