Chd8 Dosage-Sensitivity in Mature Neurons Contributes to ASD-Associated Pathology

成熟神经元中的 Chd8 剂量敏感性有助于 ASD 相关病理学

基本信息

批准号：
9760260
负责人：
Alexandria Ayanna Wade
金额：
$ 3.74万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9760260
关键词：
Address Alleles Automobile Driving Autopsy Behavior Behavioral Behavioral Assay Biological Biology Brain Brain region Cell physiology Cerebellum Chromatin Chromatin Remodeling Factor Chromatin Structure Cognitive DNA DNA-Binding Proteins Data Development Diagnosis Embryo Engineering Essential Genes Eukaryotic Cell Exons Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Transcription Genetic study Genome Genomics Germ-Line Mutation Goals Hippocampus (Brain)Impaired cognition Impairment Intellectual functioning disability Intervention Knowledge Life Link Locomotion Mus Mutant Strains Mice Mutation Neurobiology Neurodevelopmental Disorder Neurons Pathogenicity Pathology Pathology Report Patients Pattern Pharmacology Phenotype Play Process Protein Isoforms Publications Publishing Reporting Research Role Schizophrenia Site Spliced Genes Synapses Testing Work attenuation autism spectrum disorder base body system calmodulin-dependent protein kinase II cell type chromatin remodeling cohort conditional mutant conditioned fear dosage gene repression helicase improved interest loss of function mutation mouse development mouse model neurodevelopment novel object recognition postnatal preference social synaptic function transcriptome sequencing

项目摘要

Research Plan Abstract Chromatin structure controls the global and local transcriptional potential of the genome, enabling the diversification of eukaryotic cell types and function through finely-tuned gene expression patterns. Unlike DNA itself, chromatin is dynamic, enabling changes in functional readout of the genome based on the activity of chromatin remodeling factors (CRFs). Despite the central role of chromatin remodeling in guiding activation and repression of gene expression in the development and function of the mammalian brain, critical gaps remain in our understanding about the role of most CRFs. In the past decade, case sequencing studies have revealed the surprising finding that single copy loss-of-function mutations of numerous CRFs are major causal factors in neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD), schizophrenia, and intellectual disability. Chromodomain helicase DNA binding protein 8 (CHD8) is a CRF with one of the highest observed de novo loss-of-function mutations rates in patients with ASD, with mutations also described in patients with schizophrenia and intellectual disability, making it a gene of high relevance. While genetic studies have made clear that haploinsufficiency of CRFs such as CHD8 represent a strong contributing factor in neurodevelopmental disorders, the mechanisms driving pathology in the embryonic and postnatal brain remain unknown. This lack of functional characterization represents a critical barrier to understanding the role of CRFs in normal and pathogenic processes in the brain. CHD8 is an essential gene during mouse development and CHD8 haploinsufficiency has been shown to impact early neurodevelopment. However, work in mouse models has also shown that Chd8 haploinsufficiency leads to synaptic pathology. Published mouse models of Chd8 have focused on constitutive germline mutation, making it impossible to disentangle developmental from postnatal requirements for Chd8 or to define cell-type specific effects of Chd8 mutation in neurons. My research will address this key gap in knowledge, defining region-specific perturbations to transcription in the mouse brain caused by Chd8 haploinsufficiency and testing whether conditional Chd8 mutation in postnatal neurons is sufficient to recapitulate NDD-relevant transcriptional and behavioral pathology reported in mice with constitutive germline Chd8 mutations. This work will definitively address a central question in the field relevant to understanding how CRF mutations cause behavioral pathology: whether cognitive and behavioral pathology is caused by developmental perturbation or, alternatively, if pathology is caused by disruption to ongoing requirement for Chd8 expression in mature neurons. The results from this study will significantly improve knowledge of the role of CHD8, and more generally CRFs, in the brain and as a causal factor in NDDs. Towards eventual improvements in diagnosis and treatment of NDDs, characterizing how CHD8-dependent chromatin remodeling activity contributes to synaptic pathology in neurons could reveal novel postnatal pharmacological interventions for both patients with CHD8 mutations and for patients with mutations to CRFs in general.

研究计划摘要染色质结构控制基因组的全球和局部转录潜力，使得能够通过精细调整的基因表达模式的真核细胞类型和功能的多样化。与DNA不同本身，染色质是动态的，可以根据基因组的功能读数的变化染色质重塑因子（CRF）。尽管染色质重塑在引导激活和抑制基因表达在哺乳动物大脑的发育和功能中，临界缺口仍然存在我们对大多数CRF的作用的理解。在过去的十年中，案例测序研究揭示了令人惊讶的发现，众多CRF的单个功能丧失突变是主要因果因素神经发育障碍（NDD），例如自闭症谱系障碍（ASD），精神分裂症和智力残疾。染色体构想酶DNA结合蛋白8（CHD8）是CRF，具有最高观察到的DE之一 ASD患者的NOVO功能丧失突变率，在患者中也描述了突变精神分裂症和智力残疾，使其成为高度相关的基因。而遗传研究已经进行清楚地表明，诸如CHD8之类的CRF的单倍不足是神经发育的强大因素疾病，驱动胚胎和产后大脑病理学的机制仍然未知。这种缺乏功能表征代表了了解CRF在正常和大脑中的致病过程。 CHD8是小鼠发育过程中的重要基因和CHD8 单倍不足已被证明会影响早期神经发育。但是，在鼠标模型中工作也有表明CHD8单倍不足会导致突触病理。已发布的CHD8的鼠标模型已集中关于本构种系突变，使得不可能从产后摆脱发育 CHD8的要求或定义神经元中CHD8突变的细胞类型特异性作用。我的研究会在知识上解决此关键差距，定义了针对小鼠大脑转录的区域特异性扰动由CHD8单倍不足且测试产后神经元中有条件的CHD8突变是否为足以概括与本构的小鼠报道的与NDD相关的转录和行为病理学种系CHD8突变。这项工作将一定要解决与该领域的核心问题了解CRF突变如何引起行为病理：认知和行为病理是否是由发育扰动引起的，或者，如果病理是由持续的破坏引起的成熟神经元中CHD8表达的需求。这项研究的结果将大大改善了解CHD8和更普遍的CRF在大脑中的作用以及NDD中的因果因素。向最终改善了NDD的诊断和治疗，表征CHD8依赖性染色质的方式重塑活性有助于神经元突触病理学，可能揭示出新的产后药理学两位CHD8突变患者的干预措施以及对CRF的突变患者的干预措施。