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，这些亚基在散发性精神发育迟滞和散发性自闭症中经常突变。此外，神经元特异性Brg 1相关因子（nBAF）核小体重塑复合物的各种亚基中的从头突变与Coffin-Siris和Nicolaides-Baraitser综合征有关，这两种综合征都与智力残疾有关。总之，这些研究表明，nBAF功能是正常认知功能所必需的。核小体重塑复合物通过将核小体重新定位在基因启动子处来修饰染色质结构并调节表达。为什么BAF复合物突变对染色质重塑的干扰会导致认知功能障碍尚不清楚。 虽然核小体重塑在其他领域（如酵母遗传学和癌症）是一个重要的课题，但在神经科学中却很少受到关注。然而，一项重大发现是鉴定出第一个神经元特异性BAF复合物，随后发现该复合物可以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复合物具有亚基BAF 53 b，其参与产生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对突触生理和行为的潜在贡献的理想靶标。基于这一点，我们建议测试的假设，BAF 53 b，在神经元的命运决定在发展过程中发挥了关键作用后，继续调节基因表达，这样做的方式至关重要的成人可塑性和记忆。 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研究BAF 53 b在长期记忆中的作用。在目标2中，我们将研究BAF 53 b在长时程增强（突触可塑性的一种形式）中的作用。在目标3中，我们将使用下一代测序，RNA seq，以确定在记忆巩固过程中BAF 53 b调节哪些基因表达谱。总之，这些目标下的工作将阐明BAF 53 b和nBAF复合物对记忆过程的贡献，从而大大有助于理解复合物中的突变如何导致人类认知障碍。