Notch Target Gene Regulation in Normal and Malignant T Cells

正常和恶性 T 细胞中的 Notch 靶基因调控

基本信息

批准号：
8558597
负责人：
WARREN S PEAR
金额：
$ 27.78万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-18 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8558597
关键词：
Acute T Cell Leukemia Antibodies Binding Binding Sites Bioinformatics Cell Line Cell Nucleus Cell membrane Cells Chromatin Complex DNA Binding Data Defect Development Dimerization Disease Epigenetic Process Family Freezing Funding Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genome Genomics Goals Head Histones Human IL2RA gene Investigation Ligands Malignant - descriptor Malignant Neoplasms Measures Mediating Molecular Multipotent Stem Cells Mus Mutation Names Nuclear Oncogenes Oncogenic Pathogenesis Pathway interactions Pattern Play Response Elements Role Signal Transduction Site Staging T-Cell Development T-Cell Transformation T-Lymphocyte Technology To specify Toxic effect Work base epigenome gain of function genome-wide in vivo insight leukemia leukemogenesis mutant notch protein novel progenitor programs receptor thymocyte transcription factor vertebrate genome

项目摘要

Notchl's oncogenic activity in T cell progenitors appears to represent an exaggeration of its normal functions during T cell development. We will use new ChlP-Seq and bioinformatic technologies to delineate the interaction of Notchl with the genomes of normal murine and human thymocytes. By correlating these interactions with chromatin marks and gene expression, we will gain a global view of how Notchl regulates T cell development, and by comparing these interactions with those of Notchl in murine and human T-ALLs, we will further gain a deep understanding of key similarities and differences between normal and malignant thymocytes. A second key aspect of Notchl interaction with normal and malignant thymocytes is regulation of gene expression through sequence-paired binding sites (SPSs) for the transcription factor CSL that permit Notchl dimerization. Mutants that disrupt dimeric Notch complexes cannot induce T-ALL, show defects in T cell development, and lose the ability to upregulate key target genes such as Myc and pTa. These complementary lines of investigation will be pursued through two aims: Aim 1; To determine how Notchl regulates T cell development. We will combine ChlP-Seq with computational approaches to identify Notch1/CSL binding sites genome-wide, characterize the specific response elements that control transcription of key Notch target genes, identify both novel Notchl target genes, and elucidate mechanisms used by Notch to regulate p-selection and other stages of T cell development. In addition, the epigenetic landscapes of normal stages of T cell development will be compared to T-ALL cells. Aim 2: To determine the role of dimeric Notch signaling complexes in T-ALL. We will identify and validate dimerization-dependent Notch targets and determine the in vivo importance of dimerization-dependent Notch signaling during T cell development. Together, these studies will provide a comprehensive molecular and genomic understanding of how Notch regulates T cell development and T cell transformation, and in doing so provide new opportunities to rationally target the Notch pathway in T-ALL and other diseases.

Notchl在T细胞祖细胞中的致癌活性似乎代表了其正常的夸张 T细胞发育过程中的功能。我们将使用新的CHLP-seq和生物信息学技术来描述 Notchl与正常鼠和人胸腺细胞的基因组的相互作用。通过将这些关联与染色质标记和基因表达的相互作用，我们将获得Notchl如何调节的全局视图 T细胞的发展，并通过将这些相互作用与鼠和人类T-alls中的Notchl进行比较，我们将进一步了解正常和恶性之间的关键相似性和差异胸腺细胞。 Notchl与正常和恶性胸腺细胞相互作用的第二个关键方面是调节基因通过转录因子CSL的序列对结合位点（SPSS）的表达，允许Notchl 二聚化。破坏二聚体凹配合物的突变体不能诱导T-all，在T细胞中显示缺陷开发，失去上调关键靶基因（例如MYC和PTA）的能力。这些互补的调查路线将通过两个目的进行：目标1;确定Notchl如何调节T细胞的发育。我们将将Chlp-seq与识别Notch1/CSL结合位点基因组的计算方法，表征了特定控制关键缺口靶基因转录的响应元素，识别两个新型Notchl靶标基因和阐明Notch使用的机制来调节p选择和其他T细胞的其他阶段发展。此外，T细胞发育正常阶段的表观遗传景观将是与T-ALL细胞相比。 AIM 2：确定二聚体Notch信号复合物在T-ALL中的作用。我们将识别并验证依赖于二聚体的凹槽目标，并确定依赖于二聚体的体内重要性 T细胞发育过程中的缺口信号传导。总之，这些研究将为缺口提供全面的分子和基因组理解调节T细胞开发和T细胞转换，并为此提供新的机会理性地针对T-ALL和其他疾病中的Notch途径。