Interpreting and Deploying Genomic Information During Animal Development

动物发育过程中基因组信息的解释和应用

• 批准号: 10383722
• 负责人: RICHARD S MANN
• 金额: $ 63.06万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-03 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383722
• 关键词: Animals; Attention; Binding Sites; Cells; Code; DNA Binding; DNA Binding Domain; Defect; Development; Diabetes Mellitus; Embryonic Development; Family; Funding; Genes; Genetic Transcription; Genomics; Goals; HOX protein; Homeodomain Proteins; In Vitro; Invertebrates; Leg; Malignant Neoplasms; Mutation; Play; Post-Translational Protein Processing; Proteins; Resolution; Role; Specificity; Vertebrates; Wing; appendage; cofactor; experimental study; homeodomain; human disease; in vivo; member; mutant; novel; organ growth; programs; transcription factor; whole genome

Summary The long term goal of this project is to understand how members of large transcription factor families, which share a DNA binding domain and typically have very similar DNA binding specificities, execute highly specific functions in vivo. The primary focus of this proposal is on the Hox family of homeodomain transcription factors, which play critical roles during animal embryogenesis, organ development, and appendage specification in both vertebrates and invertebrates. When these transcription factors mis-regulate their target genes, either due to mutations in their protein-coding sequences or in their target DNA binding sites, developmental defects and many human diseases, from cancer to diabetes, can result. For the next funding period this project will bridge the gap between understanding how these factors specifically recognize their binding sites in vitro, often in conjunction with cofactors, and how they execute their specific functions in vivo. This will be accomplished using whole genome approaches with tagged and mutant Hox factors and by visualizing these proteins and their binding sites in living cells. Additional efforts will be to identify and characterize newly discovered novel cofactors and mechanisms, such as post-translational modifications of Hox proteins, that can alter their DNA binding specificities and/or transcriptional regulatory activities in vivo. In all cases, these experiments will be grounded in identifying and understanding how Hox proteins regulate their bona fide target genes, which allow them to orchestrate entire developmental programs, such as the development of legs and wings.

概括 该项目的长期目标是了解大型转录因素的成员 具有共享DNA结合结构域并且通常具有非常相似的DNA结合的家族 特异性，在体内执行高度特定的功能。该提议的主要重点是 同源域转录因子的HOX家族，在动物期间起关键作用 脊椎动物和 无脊椎动物。当这些转录因子错误地调节其靶基因时，要么是由于 其蛋白质编码序列或目标DNA结合位点的突变，发育 从癌症到糖尿病的缺陷和许多人类疾病可能会导致。下一个资金 该项目的期间将弥合理解这些因素如何具体的差距 经常与辅助因子一起识别其结合位点，以及如何执行 它们在体内的特定功能。这将使用整个基因组方法与 标记和突变的HOX因子，并通过可视化这些蛋白质及其在生物中的结合位点 细胞。额外的努力是识别和表征新发现的新型辅助因子和 机制，例如HOX蛋白的翻译后修饰，可以改变其DNA 在体内结合特异性和/或转录调节活动。在所有情况下，这些 实验将基于识别和了解HOX蛋白如何调节其调节 真正的目标基因，使他们能够协调整个开发程序，例如 作为腿和翅膀的发展。