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

H3K9 组蛋白开关；

• 批准号: 8517192
• 负责人: Rajiv Pandit Sharma
• 金额: $ 45.87万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517192
• 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; Genomics; 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，通过限制或允许 DNA 结合蛋白与基因调控序列的附着来转导环境事件对转录组的影响。 H3K9 组蛋白双峰开关对于将“限制性”(DimH3K9) 或“允许性”(AceH3K9) 染色质组装到基因组的基因丰富区域至关重要。该提议的核心假设是，在精神分裂症中，染色质会向更受限制的状态平衡。这具有直接的临床后果，因为基因组 DNA 与限制性染色质隔离，转录效率低下，这可能解释了对突触精神药理学的临床反应不佳，而且还因为组蛋白共价修饰可以用小分子药理学靶向。具体目标将研究以下假设：a) H3K9 开关有差异地处于限制状态 (DimH3K9) 存在于精神分裂症患者的血液和大脑中； b) 测量活体患者外周血中 H3K9 的水平，将鉴定出具有较低允许状态 (AceH3K9) 水平的同质样本，该样本将优先对丙戊酸等临床 HDAC 抑制剂做出反应。染色质结构和功能将在来自哈佛大脑收藏的死后大脑样本和从三个诊断组获得的活体患者的循环血液单核细胞（PBMC）中进行检查； i) 正常人，ii) 精神分裂症（首发和慢性），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。来自死后大脑 ChIP-seq 实验的数据将揭示被这种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 在诊断组之间验证和比较 DimH3K9 抑制网络的 mRNA 输出。在活体患者中，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（因此具有较高水平的限制性染色质）的受试者将被随机分配到 HDAC 抑制剂丙戊酸（加巴喷丁作为抗惊厥对照）的对照试验中，以探索能够“放松”的药物的治疗潜力染色质。在该项目结束时，我们将对两种主要精神疾病的染色质组装进行调查，并回答与临床人群中表观遗传基因调控相关的几个问题。同样重要的是，我们开始将已发表的细胞、动物和死后大脑研究结果转化为具有重大理论和治疗意义的领域的活体临床人群。