Tet1 activity and function in helper T cells

辅助 T 细胞中的 Tet1 活性和功能

基本信息

批准号：
8754547
负责人：
Amy Susan Weinmann
金额：
$ 18.38万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8754547
关键词：
Address Area BTB/POZ Domain CD4 Positive T Lymphocytes Cell Lineage Cells Complex Cytosine DNA DNA Modification Process DNA Packaging DNA biosynthesis Data Development Disease Enzymes Epigenetic Process Event Excision Future Gene Expression Gene Expression Regulation Gene Mutation Gene Targeting Genes Genome Genomics Goals Helper-Inducer T-Lymphocyte Hematopoietic Neoplasms High Prevalence Histones Immune Immune response Immune system Influenza Interleukin-2 Knowledge Malignant Neoplasms Mammalian Cell Mediating Memory Methylation Modification Molecular Profiling Mutation Nucleic Acid Regulatory Sequences Organism Pattern Phenotype Play Ploidies Population Process Protein Family Protein translocation Proteins Recruitment Activity Repression Research Research Priority Role Site Specific qualifier value Specificity Structure of germinal center of lymph node T cell differentiation T cell response T memory cell T-Cell Development T-Lymphocyte Testing Therapeutic Intervention Time Tissue-Specific Gene Expression Virus Diseases base cell type cellular development demethylation flexibility histone modification human disease insight leukemia/lymphoma novel programs promoter public health relevance research study response transcription factor vaccination strategy

项目摘要

DESCRIPTION (provided by applicant): The importance of properly establishing and maintaining epigenetic states in cellular development is unmistakable. The critical role for this process is highlighted by the number of mutations in epigenetic modifying proteins that are associated with human diseases, with a particularly high prevalence found in cancers. Similarly in the immune system, the precise coordination of epigenetic events is also required for cellular differentiation, and blood cancers such as leukemia and lymphoma often have mutations that impact the functions of epigenetic-modifying complexes. Recent research efforts have focused on profiling epigenetic modifications to define their cell-type and activation-state specific distribution. There also has been an emphasis on correlating changes in epigenetic patterns with human disease states. However, a major gap in our current knowledge has been defining the events that control the site specific targeting of the enzymatic machinery that regulates epigenetic patterns in unique cellular states. This is a high impact area of research because cell-type and activation-state specific epigenetic patterns cannot be explained without knowledge of the mechanisms that direct epigenetic-modifying complexes to unique sites in different cellular contexts. The focus of this proposal will be on the site-specific genomic targeting and functional activity of the DNA- demethylase Tet1 in helper T cells. Until recently, i was unclear if a cell possessed enzymatic machinery with the potential to actively remove the methyl modification on cytosine bases within the DNA. Some of the first hints that active DNA demethylation occurs in mammalian cells came from studies in T cells examining the IL-2 promoter, where the DNA replication-independent removal of cytosine methylation modifications was experimentally observed. The discovery of the ten-eleven-translocation (TET) protein family provided the first evidence that cytosine methylation could be broken down by a cellular enzyme into a hydroxymethylated state, with the potential to then be successively converted to the unmethylated state. Notably, mutations in TET proteins are found in a number of blood cancers, highlighting the importance of this protein family in immune cell development. In this proposal, we will for the first time define the mechanisms that target Tet1 to specific genomic loci in helpe T cells and its importance in the immune response. These studies will form the basis for understanding the site-specific targeting of Tet1 to loci in helper T cell development and how this impacts cellular transitions as well as the functional potential of the cells during an immune response to viral infection.

描述（由申请人提供）：在细胞发育中正确建立和维持表观遗传状态的重要性是明确的。该过程的关键作用是由与人类疾病相关的表观遗传修饰蛋白中突变的数量突出的，并且在癌症中发现了特别高的患病率。同样，在免疫系统中，细胞分化也需要表观遗传事件的精确配位，而血液癌（例如白血病和淋巴瘤）通常具有影响表观遗传修饰复合物功能的突变。最近的研究工作重点是分析表观遗传修饰，以定义其细胞类型和激活状态特定分布。还强调将表观遗传模式的变化与人类疾病状态相关联。但是，我们当前知识的一个主要差距是定义了控制位点特定靶向酶促机制的事件，该酶机制调节独特的细胞状态的表观遗传模式。这是一个很高的研究领域，因为如果没有了解将表观遗传修饰复合物直接在不同细胞环境下将复合物引导到独特位点的机制，则无法解释细胞类型和激活状态特定的表观遗传模式。该建议的重点将放在辅助T细胞中DNA-甲基酶TET1的位点特异性基因组靶向和功能活性上。直到最近，我还不清楚一个细胞是否具有酶促机制，可能会在DNA内的胞嘧啶碱基上积极去除甲基修饰。在哺乳动物细胞中发生活性DNA脱甲基化的一些最初暗示来自研究IL-2启动子的T细胞的研究，其中在其中观察到了胞质甲基化修饰的DNA复制非依赖性去除。十个时期 - 转换（TET）蛋白家族的发现提供了第一个证据，表明胞嘧啶甲基化可以通过细胞酶分解为羟基甲基化态，然后将其连续转化为未甲基化的状态。值得注意的是，在许多血液癌中发现了TET蛋白的突变，突出了该蛋白质家族在免疫细胞发育中的重要性。在此提案中，我们将首次定义将TET1定义为有助于T细胞中特定基因组基因座的机制及其在免疫反应中的重要性。这些研究将构成理解TET1特异性靶向辅助T细胞开发中的位点特异性靶向，以及这如何影响细胞过渡以及免疫期间细胞的功能潜力对病毒感染的反应。