Ikaros-based epigenetic regulation of T cell leukemogenesis

描述(由申请人提供)：DNA结合因子Ikaros及其与核小体重塑和脱乙酰酶(NuRD)复合体相关的染色质重塑控制着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进入这一发育过程的表观遗传调控的切入点。这种以Ikaros为基础的表观遗传机制的崩溃干扰了T细胞的成熟，并导致T细胞白血病的快速发展，其界限是Notch信号的激活。这一过程和涉及的机制是我们目前调查的重点。在目标1中，我们通过检测Ikaros功能丧失与其邻近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在设定染色质环境中的作用。这里将收集几个重要的见解，例如Ikaros在设定表观遗传密码中的作用，在调控控制正常发育的基因网络和信号通路方面的作用，以及这些如何被颠覆以促进白血病的发展。我们还测试了T细胞成熟过程中白血病发展潜力的变化是由于Ikaros基因靶点的变化，还是由于它们的表观遗传状态和调节模式的变化。在目标2中，我们更深入地研究Ikaros调节染色质可及性的中央机制。我们测试了Ikaros与其染色质重塑伙伴Mi-22在决定局部核小体动力学和作用部位的组蛋白修饰以及Ikaros的DNA结合在这一过程中的作用方面的拮抗作用。我们考察了伊卡洛斯是促进还是阻止了也针对其邻近社区的其他因素的获取。T-ALL中激活的信号通路通过翻译后修饰靶向Ikaros的DNA结合，被研究为改变NuRD复合体的染色质重塑输出以实现发育过程中基因表达快速变化的潜在关键。基于Ikaros的表观遗传机制及其控制的功能基因网络，从我们提出的研究中推导出来，将为控制T细胞分化的正常和异常阶段提供手段。重要的是，这些研究可能在未来支持T-ALL治疗的智能/定制疗法的设计。

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.