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

• 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
• 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

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 来自精神分裂症最近全外显子组测序研究的集体数据 证实了基因破坏性从头功能丧失突变的显着富集 并导致了SETD 1A的贡献，它编码组蛋白 甲基转移酶。值得注意的是，SETD 1A突变导致疾病风险大幅增加， 这为疾病建模提供了一个很好的起点。 将SETD 1A作为SCZ风险基因的无菌鉴定强调了 神经基因调控在精神分裂症遗传结构中的作用， 与支持监管重要作用的累积证据相一致 神经精神疾病风险的常见和罕见变异。这一发现也是 这与几条证据一致，表明组蛋白甲基化更重要， 包括最近观察到的组蛋白甲基化 在GWAS的4，939个生物学途径中显示了最强的统计富集 精神疾病的数据。事实上，常见和罕见的风险变异 聚集体在这一特定的生物学途径中的作用突出了其对 精神分裂症然而，现阶段还不清楚如何翻译无处不在的 分子过程，如染色质修饰成一个机制和疾病- 具体的见解。在这方面，SETD 1A调查结果提供了一个句柄，一个起点， 以此来建立模型并检验假设。 这项提案的目标是解决关键问题，即染色质 调节缺陷在SCZ的发病机制中发挥作用，通过（i）研究 Setd 1a对小鼠认知和突触功能的发育要求以及Setd 1a对小鼠认知和突触功能的影响 受其缺陷影响的神经回路的性质（ii）识别直接神经元 Setd 1a在前额叶皮层中的靶点，以及（iii）生成和分析人类 SETD 1A缺陷皮质神经元。 对精神疾病中染色质调节的拟议研究的最终目标是 了解基因脆弱性何时/何地/如何影响基因表达， 塑造大脑回路和功能。拟议中的研究还将揭示一个主机 精神分裂症的候选基因，并承诺在我们的重要进展 理解，诊断和治疗衰弱性精神疾病，如 精神分裂症