Genome-wide networks that modulate the T-lineage cell fate

调节 T 谱系细胞命运的全基因组网络

• 批准号: 8608279
• 负责人: CORNELIS MURRE
• 金额: $ 38.22万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608279
• 关键词: Affect; Antigen Receptors; Attenuated; B-Cell Development; Binding Sites; Cell Lineage; Cells; Chromosomes; Complex; DNA Binding; DNA Sequence Rearrangement; Development; E protein; Enhancers; Epithelial; Exclusion; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genome; Genomics; Global Change; Goals; Helix-Turn-Helix Motifs; Immune System Diseases; Instruction; Link; Location; Malignant Neoplasms; Mediating; Molecular; Names; Nuclear; Pathway interactions; Play; Population; Process; Protein Family; Proteins; Role; Series; Signal Transduction; Structure; Switch Genes; T-Cell Development; T-Lymphocyte; TCF3 gene; base; genome wide association study; genome-wide; helix-loop-helix protein differentiation inhibitor; member; notch protein; novel; preference; progenitor; programs; promoter; response; thymocyte; transcription factor

The long-range goals of our studies are to understand the mechanisms that enforce the γδT and pre-TCR checkpoints. We would like to describe these checkpoints in terms of global networks involving transcriptional regulators, signaling components and survival factors. Previously, we as well as others have demonstrated that E- and Id-proteins play critical roles in enforcing the γδ, pre-TCR and TCR checkpoints. Most prominent among the E-proteins are the E2A gene products, E12 and E47. Two additional members that are closely related to E2A, named E2-2 and HEB, also belong to the E-protein family. The DNA binding activities of E-proteins are attenuated by a subset of helix-loop-helix (HLH) proteins, named ld1-4. E-proteins levels are high in T cell progenitors where they initiate TCRy, δ as well β locus rearrangement, activate the expression of genes encoding for proteins involved in Notch- and pre-TCR signaling arid antagonize proliferation. Once a γδ or pre-TCR complex is assembled, IdS levels are elevated to suppress E2A DNA binding. Here we propose to continue these studies. We would use functional studies, genome-wide analyses and computational approaches to determine the mechanisms that underpin γδ versus β selection. We would identify factors that cooperate with E-proteins to enforce the pre-TCR checkpoints. We would examine whether gradients of E-protein activity modulate DNA binding site preferences as well as enhancer repertoire selection beyond the pre-TCR checkpoint. We would examine how Notch- and pre-TCR signaling act in concert to modulate binding site as well as enhancer selection. We would describe γδ T cell development in terms of global networks of enhancer repertoires, interacting transcription factors, signaling components and survival factors. We would examine how differences in signaling by the pre- TCR and γδ TCR affect E2A occupancy and binding site selection. Finally, we would examine how these networks change during developmental progression and how such changes relate to enforcement of the γδ and pre-TCR checkpoints. RELEVANCE (See instructions): It has been established that an important population of cells, named γδ T cells, play critical roles in preserving epithelial structures that function as barriers. The proposal described here is aimed to understand the molecular mechanisms that promote their developmental progression. These studies may permit novel avenues for the treatment of immune diseases and interference with the development of malignancies.

我们研究的远程目标是了解强制执行γδT和PERE-TCR的机制 检查点。我们想根据涉及的全球网络来描述这些检查点 转录调节器，信号成分和生存因子。以前，我们和其他人 已经证明E-和ID蛋白在强制执行γδ，PER-TCR和TCR中起关键作用 检查点。 E2A基因产品E12和E47中最突出的E47。二 与E2A密切相关的其他成员，名为E2-2和HEB，也属于E蛋白 家庭。 E蛋白的DNA结合活性通过螺旋 - 环螺旋（HLH）的子集减弱 蛋白质，名为LD1-4。 e蛋白水平在T细胞祖细胞中很高，在它们启动TCRY，δ以及β基因座重排， 激活针对参与Notch-和TRE-TCR信号的蛋白质编码的基因表达 对抗增殖。一旦组装了γδ或PER-TCR复合物，IDS水平就会升高以抑制 E2a DNA结合。 在这里，我们建议继续这些研究。我们将使用功能研究，全基因组分析和 确定基础γδ与β选择的机制的计算方法。我们会的 确定与E蛋白合作以实施TCR检查点的因素。我们会检查 E蛋白活性的梯度是否调节DNA结合位点的偏好以及增强剂 曲目选择超出了TCR检查点。我们将研究Notch-和Pre-TCR 信号传导协同作用以调节结合位点以及选择增强子选择。我们将描述γδT 细胞开发在增强子库的全球网络方面，相互作用的转录因子， 信号传导成分和生存因子。我们将研究预先通过的信号传导差异 TCR和γδTCR会影响E2A的占用率和结合位点的选择。最后，我们将研究这些 网络在发育进展过程中发生变化以及这种变化的变化与γδ的实施有关 和TRE-TCR检查点。 相关性（请参阅说明）： 已经确定，一个名为γδT细胞的重要细胞群在 保存充当障碍的上皮结构。此处描述的提案的目的是 了解促进其发育进展的分子机制。这些研究可能 允许新的途径用于治疗免疫识别并干扰 恶性肿瘤。