E protein targets orchestrating γδ development and function

项目总结/摘要 T淋巴细胞包括两个主要的谱系，T淋巴细胞和T淋巴细胞，它们在宿主防御中发挥关键的、部分不同的作用。 胸腺和胸腺T细胞来自胸腺中的共同祖细胞;然而， 在胸腺发育过程中这些谱系的具体化仍不清楚，这代表了一个主要的 知识的差距。我们正在努力弥补这一知识差距。在此过程中，我们提供了令人信服的证据， T细胞受体（TCR）信号强度的差异控制着巨噬细胞和巨噬细胞T细胞命运的特化。 这些信号差异通过Id 3的成比例诱导调节命运，Id 3导致细胞凋亡的分级抑制。 E盒DNA结合蛋白（E蛋白; E2 A和HEB）的功能。为了深入了解E蛋白如何结合到 基因组在命运规范过程中被重塑，我们（所有项目）采用了一个全面的，全基因组的 该方法揭示了一些重要的见解。首先，E蛋白家族成员的抑制， 较强的TCR信号是选择性的，因为E2 A与基因组的结合被显著抑制，而HEB与基因组的结合被显著抑制。 保留（所有项目）。重要的是，保留HEB结合似乎是重要的，因为HEB功能是 产生IL-17（Proj 1/3/4）的CD 4 + T细胞的发育所需。第二，E蛋白结合紧密 与非编码转录相关，包括长链非编码RNA（lncRNA;所有项目）。我确 （项目1和4）证明了一种这样的lncRNA，ThymoD，在T细胞系中起着重要作用。 承诺.最后，在众多的调节元件中，E蛋白的占据率是 我们已经确定了两种在控制遗传变异中起关键作用的基因， 发展和功能。事实上，E蛋白与控制细胞凋亡的调节元件结合的破坏， 转录因子Tcf 7或lncRNA Gm 15417的表达增强了人外周血T细胞的成熟，并促进 采用产生IL-17的效应物命运。因此，在目前的提案中，我们将所有这些 深入阐明了E蛋白结合这些元素的变化控制的机制基础 产生IL-17的巨噬细胞T细胞的发育。深入了解控制IL-17产生的因素 T细胞至关重要，因为这些细胞与许多免疫介导的病理和癌症有关 进展为了执行这项研究计划，我们完全依赖于项目负责人的专业知识 以及基因组核心B。这一努力有望为E的作用提供很好的见解 蛋白质在控制乳腺发育和功能中的作用，这对人类健康至关重要， 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.