Ikaros-based epigenetic regulation of T cell leukemogenesis

描述（由申请人提供）：DNA结合因子Ikaros及其核小体重塑和去乙酰化酶（NuRD）复合体的染色质重塑相关物控制着T细胞分化和功能的许多关键方面，为我们研究这一发育过程的表观遗传调控提供了一个强大的切入点。这种基于ikaros的表观遗传机制的破坏会干扰T细胞成熟，并导致以Notch信号激活为界的T细胞白血病的快速发展。这一过程及其机制是我们目前调查的重点。在目标1中，我们通过检查Ikaros功能丧失与其邻近区域表现的表观遗传变化以及随后的转录变化之间的因果关系，测试Ikaros在设置染色质环境中的作用。这里将收集到一些重要的见解，比如Ikaros在设置表观遗传密码、调节控制正常发育的基因网络和信号通路中的作用，以及这些如何被破坏以导致白血病的发展。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由于Ikaros基因靶点的变化还是由于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，在其作用位点决定局部核小体动力学和组蛋白修饰，以及Ikaros的DNA结合在这一过程中的作用。我们研究伊卡洛斯是否促进或抑制其他因素也针对其邻近地区。T-ALL中激活的信号通路通过翻译后修饰靶向Ikaros的DNA结合，作为改变NuRD复合体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，将为操纵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为T-ALL治疗的智能/定制疗法设计提供支持。

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.