Interpreting and Deploying Genomic Information During Animal Development

总结 该项目的长期目标是了解大转录因子的成员如何 家族，共享DNA结合结构域，通常具有非常相似的DNA结合 特异性，在体内执行高度特异性的功能。本提案的主要重点是 同源异型域转录因子Hox家族在动物生长发育中起着重要作用， 胚胎发生，器官发育，以及脊椎动物和 无脊椎动物当这些转录因子错误调节其靶基因时，无论是由于 其蛋白质编码序列或其靶DNA结合位点中的突变，发育 可能会导致缺陷和许多人类疾病，从癌症到糖尿病。下一次融资 在此期间，本项目将弥合理解这些因素具体如何之间的差距 在体外识别它们的结合位点，通常与辅因子结合，以及它们如何执行 它们在体内的具体功能。这将使用全基因组方法来实现， 标记和突变的Hox因子，并通过可视化这些蛋白质及其结合位点， 细胞其他的努力将是鉴定和表征新发现的新型辅因子， 机制，如Hox蛋白的翻译后修饰，可以改变它们的DNA 结合特异性和/或体内转录调节活性。在所有情况下，这些 实验将基于识别和理解Hox蛋白如何调节它们的功能。 真正的目标基因，这使他们能够协调整个发展计划， 就像腿和翅膀的发展一样。

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.