Ikaros-based epigenetic regulation of T cell leukemogenesis

基于 Ikaros 的 T 细胞白血病发生的表观遗传调控

• 批准号: 8464910
• 负责人: KATIA GEORGOPOULOS
• 金额: $ 4.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464910
• 关键词: Binding Sites; CD8B1 gene; Calcineurin; Cell Maturation; Cell physiology; Cells; Cessation of life; Chromatin; Code; Communication; Complex; DNA Binding; DNA-Binding Proteins; Deacetylase; Decision Making; Development; Developmental Biology; Developmental Process; Disease; Distal; Environment; Enzymes; Epigenetic Process; Event; Family; Future; Gatekeeping; Gene Expression; Gene Silencing; Gene Targeting; Generations; Genes; Genetic Transcription; Glean; Histones; Homeostasis; Human; Investigation; Lead; Lymphocyte; Lymphoid; Maintenance; Malignant Neoplasms; Mature T-Lymphocyte; Mediating; Minor; Modeling; Neighborhoods; Nuclear; Nucleosomes; Output; Pathway interactions; Phase; Phenotype; Polycomb; Population; Post-Translational Protein Processing; Process; Proliferating; Recruitment Activity; Regulation; Role; Signal Pathway; Signal Transduction; Site; Staging; Surface; T cell differentiation; T cell regulation; T-Cell Development; T-Cell Leukemia; T-Cell Receptor; T-Lymphocyte; Testing; Time; Transcriptional Regulation; Vertebral column; Work; Zinc Fingers; base; chromatin remodeling; design; empowered; genome-wide; histone modification; insight; leukemia; leukemogenesis; loss of function; mutant; notch protein; promoter; receptor; response; thymocyte

DESCRIPTION (provided by applicant): The DNA binding factor Ikaros and its chromatin remodeling associates of the Nucleosome Remodeling and Deacetylase (NuRD) complex control many key aspects of T cell differentiation and function providing us with a formidable entry point into the epigenetic regulation of this developmental process. Breakdown in this Ikaros-based epigenetic machinery interferes with T cell maturation and result in rapid development of T cell leukemia demarcated by activation of Notch signaling. This process and the mechanisms involved are the focus of our current investigation. In aim 1, we test the role of Ikaros in setting chromatin environments by examining the cause-effect relationship between Ikaros-loss-of-function and the epigenetic changes manifested in its immediate neighborhood as well as the transcriptional changes that follow. Several important insights are to be gleaned here, such as the role of Ikaros in setting epigenetic code, in regulating gene networks and signaling pathways that control normal development and how these are subverted for leukemia development. We also test whether a change in the potential for leukemia development seen during T cell maturation is due to a change in Ikaros gene targets or in their epigenetic state and mode of regulation. In aim 2, we go deeper into the central mechanism by which Ikaros regulates chromatin accessibility. We test Ikaros' antagonism with its chromatin remodeling associate, Mi-22, in dictating local nucleosome dynamics and histone modifications at their sites of action and the role of Ikaros' DNA binding in this process. We examine whether Ikaros promotes or inhibits access to other factors that also target its immediate neighborhood. The role of signaling pathways activated in T-ALL in targeting Ikaros' DNA binding through post-translational modifications is investigated as a potential key to altering the chromatin remodeling output of the NuRD complex to achieve rapid changes in gene expression during development. The Ikaros-based epigenetic mechanisms and the functional gene networks they control, deduced from our proposed studies will provide the means to manipulate both normal and aberrant stages of T cell differentiation. Importantly, these studies may in the future empower the design of intelligent/tailored therapies for T-ALL treatment.

描述（由申请人提供）：DNA结合因子Ikaros及其核小体重塑和脱乙酰酶（NuRD）复合物的染色质重塑相关物控制T细胞分化和功能的许多关键方面，为我们提供了进入该发育过程的表观遗传调控的强大切入点。这种基于Ikaros的表观遗传机制的破坏干扰T细胞成熟，并导致通过Notch信号传导的激活划分的T细胞白血病的快速发展。这一过程及其机制是我们目前研究的重点。在目标1中，我们通过检查Ikaros功能丧失与其紧邻的表观遗传变化以及随后的转录变化之间的因果关系来测试Ikaros在设置染色质环境中的作用。在这里可以收集到几个重要的见解，例如Ikaros在设置表观遗传密码中的作用，在调节控制正常发育的基因网络和信号通路中的作用，以及这些是如何被颠覆为白血病发展的。我们还测试了在T细胞成熟过程中观察到的白血病发展潜力的变化是否是由于Ikaros基因靶点的变化或其表观遗传状态和调节模式的变化。在目标2中，我们深入研究了Ikaros调节染色质可及性的中心机制。我们测试了Ikaros与其染色质重塑相关物Mi-22的拮抗作用，以决定局部核小体动力学和组蛋白修饰在其作用位点以及Ikaros DNA结合在此过程中的作用。我们研究是否Ikaros促进或抑制访问其他因素，也针对其近邻。研究了T-ALL中激活的信号通路在通过翻译后修饰靶向Ikaros DNA结合中的作用，作为改变NuRD复合物染色质重塑输出的潜在关键，以实现发育期间基因表达的快速变化。基于Ikaros的表观遗传机制和它们控制的功能基因网络，从我们提出的研究中推导出来，将提供操纵T细胞分化的正常和异常阶段的手段。重要的是，这些研究可能在未来为T-ALL治疗设计智能/定制疗法。