The H3K9 HISTONE SWITCH; 'LEVELS' IN SCHIZOPHRENIA BLOOD AND BRAIN

H3K9 组蛋白开关；

• 批准号: 8857254
• 负责人: Rajiv Pandit Sharma
• 金额: $ 45.9万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857254
• 关键词: Animals; Anticonvulsants; Area; Autopsy; Basic Science; Biochemical Pathway; Bioinformatics; Bipolar Disorder; Blood; Brain; Candidate Disease Gene; Cell Culture Techniques; Cells; ChIP-seq; Chromatin; Chromatin Modeling; Chromatin Structure; Chronic; Chronic Schizophrenia; Clinical; Collection; Complex; DNA; DNA-Binding Proteins; Data; Diagnostic; Disease; Environmental Impact; Epigenetic Process; Event; Experimental Models; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Code; Genetic Transcription; Genome; Genomic DNA; Heterogeneity; Histone Deacetylase Inhibitor; Histones; Hour; Inhibitory Concentration 50; Investigation; Laboratories; Lesion; Life; Literature; Lymphocyte; Lysine; Measurement; Measures; Mental disorders; Messenger RNA; Modification; Molecular; Mononuclear; Network-based; Neurons; Nuclear Extract; Ontology; Output; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Play; Population; Population Distributions; Positioning Attribute; Process; Proteins; Psychopharmacology; Publishing; Randomized; Relaxation; Resistance; Role; Sampling; Schizophrenia; Surveys; Synapses; Tail; Techniques; Therapeutic; Translations; Valproic Acid; Work; base; chromatin modification; comparative; control trial; deep sequencing; first episode schizophrenia; frontal lobe; gabapentin; genome-wide; histone modification; indexing; mRNA Expression; methyl group; novel strategies; peripheral blood; promoter; prototype; research study; response; small molecule; synaptic function

DESCRIPTION (provided by applicant): Chromatin is a complex of histone proteins and genomic DNA, and serves to transduce the impact of environmental events on the transcriptome by either restricting or permitting the attachment of DNA binding proteins to the regulatory sequences of a gene. The H3K9 histone bimodal switch is pivotal in assembling either 'restrictive' (DimH3K9) or 'permissive' (AceH3K9) chromatin to gene-rich regions of the genome. The central hypothesis for this proposal is that, in schizophrenia, chromatin equilibrates towards a more restrictive state. This has direct clinical consequences because genomic DNA sequestered with restrictive chromatin, is inefficiently transcribed, may explain the less than optimal clinical response to synaptic psychopharmacology, and also because histone covalent modifications can be targeted with small molecule pharmacology. The specific aims in-toto will investigate the hypotheses: a) the H3K9 switch is differentially in the restrictive state (DimH3K9) in schizophrenia patients in both blood and brain; b) measurement of peripheral 'blood levels' of H3K9 in living patients will identify a homogeneous sample with lower levels of the permissive state (AceH3K9) that will respond preferentially to a clinical HDAC inhibitor such as valproic acid. Chromatin structure and function will be examined in both, postmortem brain samples from the Harvard brain collection, and circulating blood mononuclear cells (PBMC) from living patients obtained from three diagnostic groups; i) normals, ii) schizophrenia (both first episode and chronic), iii) bipolar disorder. In the postmortem brain, we will apply genome-wide molecular techniques (ChIP-seq) to survey and analyze the distribution of DimH3K9. Data from the ChIP-seq experiments on postmortem brain will reveal gene networks that are entrained by this restrictive chromatin and have repressed mRNA transcription. Accordingly, mRNA output from DimH3K9 repressed networks will be verified and compared across diagnostic groups using qRT-PCR. In living patients, we will quantify 'blood levels' of both DimH3K9 and AceH3K9 from nuclear extracts of blood mononuclear cells; those subjects with the lowest levels of AceH3K9 (and thereby possessing higher levels of restrictive chromatin) will be randomized to a controlled trial with the HDAC inhibitor valproic acid (with gabapentin as anticonvulsant control) to explore the therapeutic potential of medications capable of 'relaxing' chromatin. At the end of this project, we would have conducted a survey of chromatin assemblies in two major mental disorders and be positioned to answer several questions relating to epigenetic gene regulation in a clinical population. Equally important we begin the translation of published findings from cell, animal and post-mortem brain investigations into living clinical populations in an area with great theoretical and therapeutic implications.

描述（由申请人提供）：染色质是组蛋白和基因组DNA的复合物，并通过限制或允许将DNA结合蛋白的附着在基因的调节序列上的附着来转导环境事件对转录组的影响。 H3K9组蛋白双峰开关在组装“限制性”（DIMH3K9）或“允许”（ACEH3K9）的染色质与基因组富基因区域的组合中至关重要。该提议的中心假设是，在精神分裂症中，染色质朝着更严格的状态平衡。这具有直接的临床后果，因为用限制性染色质隔离的基因组DNA效率低下，可以解释对突触心理学的最佳临床反应，也可以用小分子药理学来靶向组蛋白的共价修饰。特定目的在全球范围内将调查假设：a）H3K9开关在限制性状态下差异 （DIMH3K9）在血液和脑的精神分裂症患者中； b）在活着的患者中测量H3K9的外周血“血液水平”将确定具有较低水平的允许状态（ACEH3K9）的均质样品，该样本将优先响应临床HDAC抑制剂，例如丙型丙酸。染色质结构和功能将在两者中，来自哈佛大学的大脑收集后的死后大脑样本，以及从三个诊断组获得的活着的患者中循环的血液单核细胞（PBMC）； i）正常的，ii）精神分裂症（第一集和慢性发作），iii）双相情感障碍。在死后大脑中，我们将应用全基因组分子技术（CHIP-SEQ）来调查和分析DIMH3K9的分布。来自CHIP-SEQ实验的数据对事后大脑的实验将揭示该限制性染色质夹带并抑制mRNA转录的基因网络。因此，将使用QRT-PCR对DIMH3K9抑制网络产生的mRNA输出进行验证并在诊断组之间进行比较。在活着的患者中，我们将从血液单核细胞的核提取物中量化DIMH3K9和ACEH3K9的“血液水平”。那些ACEH3K9水平最低的受试者（从而拥有较高水平的限制性染色质）将被随机地与HDAC抑制剂丙乳酸（具有Gabapentin作为抗惊厥药物控制）一起进行对照试验，以探索能够“放松”染色质的药物治疗潜力。在该项目结束时，我们将对两种主要精神疾病的染色质组件进行调查，并可以回答临床人群中与表观遗传基因调控有关的几个问题。同样重要的是，我们开始翻译来自细胞，动物和验尸后的大脑调查，对具有良好理论和治疗意义的领域中的生活临床人群进行调查。