E protein targets orchestrating γδ development and function

项目摘要/摘要 T淋巴细胞包括两个主要的谱系，和，它们在宿主防御中发挥着关键的、部分不同的作用。 和T细胞来自胸腺中共同的祖细胞；然而，负责的分子过程 对于胸腺发育过程中这些血统的规范仍然不清楚，这代表了一个主要的 知识上的差距。我们寻求解决这一知识鸿沟。通过这样做，我们提供了令人信服的证据 和T细胞命运的指定受T细胞受体信号强度的差异控制。 这些信号差异通过ID3的比例诱导来调节命运，ID3导致对 E盒DNA结合蛋白(E蛋白；E2a和Heb)的功能。为了深入了解E蛋白是如何与 基因组在命运规范期间被重塑，我们(所有项目)采用了全面的、全基因组的 这一方法揭示了一些重要的见解。第一，E蛋白家族成员的抑制 强的TCR信号是选择性的，因为E2a与基因组的结合被显著抑制，而Heb结合被 保留(所有项目)。重要的是，保留Heb绑定似乎很重要，就像Heb功能一样 产生IL-17的T细胞的发育所需(项目1/3/4)。第二，E蛋白结合紧密 与非编码转录相关，包括长的非编码RNA(lncRNA；所有项目)。事实上，我们 (项目1和4)证明了这样一种名为ThymoD的lncRNA在T细胞谱系中起着重要作用。 承诺。最后，在由E蛋白占据的众多调控元件中， 在谱系承诺期间进行调节，我们已经确定了在控制方面发挥关键作用的两个 发展和功能。事实上，E蛋白与控制细胞周期的调控元件结合的中断 转录因子TCF7或LncRNAGm15417的表达促进T细胞成熟并促进 采用产生IL-17的效应器命运。因此，在目前的提案中，我们将所有这些整合在一起 阐明E蛋白与这些元件结合的变化控制的机制基础的见解 产生IL-17的T细胞的研制IL-17产生的发育控制因素研究 T细胞是至关重要的，因为这些细胞与许多免疫介导的病理和癌症有关。 进步。要执行这项研究计划，我们完全依赖项目负责人的专业知识 在该计划中，以及基因组学核心B。这一努力有望提供对E的作用的更大洞察力 蛋白质控制的发育和功能，这对人类健康和 疾病。

PROJECT SUMMARY/ABSTRACT T lymphocytes comprise two major lineages,  and , which play critical, partially-distinct roles in host defense.  and  T cells arise from a common progenitor in the thymus; however, the molecular processes responsible for specification of these lineages during development in the thymus remain unclear and this represents a major gap in knowledge. We seek to address this knowledge gap. In doing so, we have provided compelling evidence that specification of the  and  T cell fates is controlled by differences in T cell receptor (TCR) signal strength. These signaling differences regulate fate by proportional induction of Id3, which causes graded repression of the function of E box DNA binding proteins (E proteins; E2A and HEB). To gain insight into how E protein binding to the genome is remodeled during fate specification, we (all Projects) employed a comprehensive, genome-wide approach, which revealed a number of important insights. First, the repression of E protein family members by strong TCR signals is selective, in that E2A binding to the genome is markedly repressed, while HEB binding is preserved (all Projects). Importantly, the sparing of HEB binding appears to be important, as HEB function is required for development of  T cells that produce IL-17 (Proj1/3/4). Second, E protein binding is closely associated with non-coding transcription, including long non-coding RNAs (lncRNA; all Projects). Indeed, we (Projects 1 and 4) demonstrated that one such lncRNA, ThymoD, plays an essential role in T lineage commitment. Finally, from among the numerous regulatory elements whose occupancy by E proteins is modulated during  lineage commitment, we have already identified two that play critical roles in controlling  development and function. Indeed, disruption of E protein binding to regulatory elements controlling the expression of either transcription factor Tcf7 or lncRNA Gm15417 enhances  T cell maturation and promotes adoption of the IL-17 producing effector fate. Consequently, in the current proposal, we integrate all of these insights to elucidate the mechanistic basis by which changes in E protein binding to these elements controls development of IL-17 producing  T cells. Insight into the factors controlling development of IL-17 producing  T cells is critical, as these cells have been implicated in numerous immune-mediated pathologies and cancer progression. To execute this research plan, we are entirely dependent upon the expertise of the Project Leaders in the program, as well as Genomics Core B. This effort promises to provide great insight into the role of E proteins in controlling both  development and function, which is of critical importance to human health and disease.