Role of Neuron-Specific Nucleosome Remodeling in Intellectual Disability

神经元特异性核小体重塑在智力障碍中的作用

• 批准号: 9082570
• 负责人: GARY S LYNCH
• 金额: $ 2.76万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9082570
• 关键词: Actins; Adult; Animals; Attention; Autistic Disorder; Behavior; Chemosensitization; Chromatin Remodeling Factor; Chromatin Structure; Cognition; Communication; Complex; Development; Disease; Dominant-Negative Mutation; Epigenetic Process; Event; Gene Expression; Gene Expression Regulation; Genes; Health; Hippocampus (Brain); Human; Impaired cognition; Impairment; Intellectual functioning disability; Knock-out; Lead; Link; Long-Term Potentiation; Malignant Neoplasms; Memory; Memory impairment; Mental Retardation; Molecular Profiling; Mus; Mutant Strains Mice; Mutate; Mutation; N-Methyl-D-Aspartate Receptors; NURF; Neurons; Neurosciences; Nucleosomes; Phase; Physiology; Play; Proteins; Research Proposals; Role; Seminal; Short-Term Memory; Signal Transduction; Slice; Social Behavior; Synapses; Synaptic plasticity; Syndrome; Testing; Transgenic Organisms; Viral; Work; chromatin remodeling; cognitive function; exome sequencing; long term memory; memory consolidation; memory encoding; memory process; mutant; next generation sequencing; operation; precursor cell; promoter; protein complex; transcriptome sequencing; yeast genetics

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.

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已经确定了多态性BAF复合物（哺乳动物SWI/SNF染色质重塑复合物）的亚基，这些复合物经常在零星的智力低下和零星的自闭症中突变。此外，在神经元特异性BRG1相关因子（NBAF）核小体重塑复合物的各个亚基中的从头突变与棺材 - siris和Nicolaides-Baraitser综合征有关，这两种综合症都与智力残疾有关。总之，这些研究表明NBAF功能对于正常的认知功能是必需的。核小体重塑复合物可通过重新定位基因启动子来改变染色质结构并调节表达。为什么通过BAF复合物中突变对染色质重塑的干扰导致认知功能障碍是未知的。 尽管在其他领域（例如酵母遗传和癌症）中的一个重要话题，但核小体重塑对神经科学的关注很少。然而，一个主要发现是对第一个神经元特异性BAF复合物的鉴定，随后发现该复合物调节前体细胞转化为终末分化的神经元所需的基因表达。重要的是，NBAF综合体具有一个亚基BAF53B，它参与使NBAF神经元特定。该亚基既是神经元，又是NBAF复合物的特异性，使其成为研究NBAF T突触生理和行为的潜在贡献的理想目标。在这一点上，我们建议检验以下假设：BAF53B在发育过程中在神经元命运决策中发挥关键作用后，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进行。 我们提出了三个特定的目的来检验这一假设。在AIM 1中，我们将使用转基因的小鼠来检查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，这是一种突触可塑性的形式。在AIM 3中，我们将使用下一代测序RNA SEQ来确定记忆合并过程中BAF53B调节哪些基因表达谱。共同，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，从而显着有助于理解复合物中的突变如何导致人类认知障碍。