Deciphering the role of histone methyltransferase SETD1A in schizophrenia susceptibility

破译组蛋白甲基转移酶 SETD1A 在精神分裂症易感性中的作用

基本信息

批准号：
9288683
负责人：
JOSEPH A GOGOS
金额：
$ 61.44万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-02 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9288683
关键词：
Address Affect Animal Model Architecture Behavior Biological Biological Assay Brain Brain region Candidate Disease Gene Cell model Cerebral cortex Chromatin Chromatin Remodeling Factor Code Complex DNA Sequence Alteration Data Data Set Delusions Deoxyribonuclease I Development Diagnosis Disease Disease model Etiology Functional disorder Future Gene Expression Gene Expression Alteration Gene Expression Regulation Generations Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic Transcription Genome Genomics Germ-Line Mutation Goals Hallucinations Histones Human Human Genome Hypersensitivity Impaired cognition Individual Investigation Link Mental disorders Methods MicroRNAs Missense Mutation Modeling Molecular Mus Mutation Nature Neurons Nucleic Acid Regulatory Sequences Odds Ratio Pathogenesis Pathway interactions Patients Play Predisposition Prefrontal Cortex Process Property Proteins RNA Splicing Regulation Regulatory Element Research Risk Risk Estimate Role Schizophrenia Site Splice-Site Mutation Symptoms Technology Testing Transferase Translating Untranslated RNA Variant Withdrawal Work autism spectrum disorder brain circuitry brain shape chromatin modification chromatin remodeling cognitive function cognitive process design disorder risk drug development drug discovery exome sequencing frontal lobe genome wide association study genome-wide histone methylation histone methyltransferase histone modification insight loss of function mutation neural circuit neuropsychiatric disorder rare variant relating to nervous system risk variant social synaptic function

项目摘要

PROJECT SUMMARY Collective data from recent whole exome sequencing studies in schizophrenia confirmed a prominent enrichment of gene-disruptive de novo loss-of-function mutations and led to the identification of the contribution of SETD1A, which encodes for a histone methyltransferase. Notably, SETD1A mutations confer a large increase in disease risk, which provides a good starting point for disease modeling. Unambiguous identification of SETD1A as a SCZ risk gene emphasizes the important role that neural gene regulation plays in the genetic architecture of schizophrenia, consistent with accumulating evidence supporting an important role of regulatory common and rare variants in neuropsychiatric disease risk. This finding is also consistent with several lines of evidence suggesting that histone methylation is more broadly relevant to SCZ including the recent observation that histone methylation showed the strongest statistical enrichment among 4,939 biological pathways in GWAS data of psychiatric disorders. The fact that both common and rare risk variants aggregate in this particular biological pathway highlights its importance for the etiology of schizophrenia. However it is not clear at this stage how to translate a ubiquitous molecular process such as chromatin modification into a mechanistic and disease- specific insight. In this regard, the SETD1A finding provides a handle, a starting point from which to build a model and test hypotheses. The goal of this proposal is to address the critical question of how chromatin regulation deficits play a role in the pathogenesis of SCZ by (i) investigating the developmental requirement of Setd1a on cognitive and synaptic function in mice and the nature of the neural circuits affected by its deficiency (ii) identifying direct neuronal targets of Setd1a in the prefrontal cortex and (iii) generating and analyzing human SETD1A-deficient cortical neurons. The ultimate goal of the proposed studies of chromatin regulation in mental illness is to understand when/where/how genetic vulnerabilities affect gene expression in the brain and shape brain circuitry and function. The proposed studies will also reveal a host of schizophrenia candidate genes and promise important advances in our understanding, diagnosis, and treatment of debilitating psychiatric disorders, such as schizophrenia.

项目摘要来自精神分裂症的最新外显子组测序研究的集体数据确认基因干扰性de的突出功能丧失突变并导致识别setD1a的贡献，该贡献编码组蛋白甲基转移酶。值得注意的是，setD1a突变赋予了疾病风险的大幅增加，这为疾病建模提供了一个很好的起点。 SETD1A作为SCZ风险基因的明确识别强调了重要的神经基因调节在精神分裂症的遗传结构中起作用的作用，与积累支持监管的重要作用的证据一致神经精神疾病风险中常见和罕见的变体。这个发现也是与几条证据一致，表明组蛋白甲基化更多与SCZ广泛相关，包括最近观察到组蛋白甲基化在GWAS中的4,939个生物途径中显示出最强的统计富集精神疾病的数据。常见和稀有风险变体这一事实在这一特定的生物学途径中的总体上突出了其对病因的重要性精神分裂症。但是，在这个阶段尚不清楚如何翻译无处不在的分子过程，例如染色质修饰为机械和疾病 - 具体的见解。在这方面，setD1a发现提供了一个手柄，一个起点从中构建模型和检验假设。该建议的目的是解决染色质的关键问题调节缺陷在（i）研究中在SCZ的发病机理中起作用 SETD1A对小鼠的认知和突触功能的发展需求受其缺乏影响的神经回路的性质（ii）识别直接神经元 setD1a的靶标在前额叶皮层中，（iii）生成和分析人类 SETD1A缺乏皮质神经元。拟议对精神疾病中染色质调节的研究的最终目标是了解何时/何处/遗传脆弱性如何影响基因表达脑和脑电路和功能。拟议的研究还将揭示宿主精神分裂症候选基因和承诺在我们的重要进展理解，诊断和治疗衰弱的精神疾病，例如精神分裂症。