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

基本信息

批准号：
8978293
负责人：
KATIA GEORGOPOULOS
金额：
$ 34.22万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8978293
关键词：
Acute T Cell Leukemia 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 Development T-Cell Leukemia T-Cell Receptor T-Lymphocyte Testing Time Transcriptional Regulation Vertebral column Work Zinc Fingers base chromatin remodeling design empowered epigenetic regulation genome-wide histone modification insight leukemia leukemia treatment leukemogenesis loss of function mutant notch protein promoter receptor response thymocyte

项目摘要

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-2ß, 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关联物控制 T 细胞分化和功能的许多关键方面，为我们提供了一个强大的切入点来了解 T 细胞的表观遗传调控。这种基于 Ikaros 的表观遗传机制的崩溃会干扰 T 细胞的成熟，并导致 T 细胞白血病的快速发展，其特征是 T 细胞白血病的激活。 Notch 信号传导。在目标 1 中，我们通过检查 Ikaros 功能丧失和表观遗传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。一些重要的见解体现在它的邻近区域以及随后的转录变化中，例如 Ikaros 在设定表观遗传密码、调节基因网络和控制正常发育的信号通路中的作用。这些是如何被颠覆的我们还测试了 T 细胞成熟过程中发生白血病的可能性的变化是否是由于 Ikaros 基因靶标或其表观遗传状态和调控模式的变化所致。在目标 2 中，我们更深入地研究了核心。我们测试了 Ikaros 与其染色质重塑伙伴 Mi-2ß 的拮抗作用，以决定其位点的局部核小体动力学和组蛋白修饰。我们研究了 Ikaros 是否促进或抑制了 T-ALL 中激活的信号通路在靶向 Ikaros DNA 结合中的作用。翻译修饰被研究为改变 NuRD 复合体染色质重塑输出的潜在关键，以实现发育过程中基因表达的快速变化，这是从我们提出的研究中推导出来的基于 Ikaros 的表观遗传机制及其控制的功能基因网络。将提供操纵 T 细胞分化的正常和异常阶段的方法。重要的是，这些研究可能在未来为 T-ALL 治疗的智能/定制疗法的设计提供支持。