Regulation of the Gli protein TRA-1 by co-factors

Gli蛋白构成了一组重要但复杂的转录因子。人类有三个基因，它们的突变或调控错误可能会导致发育障碍或癌症。我们对这些蛋白质的理解建立在对它们的果蝇的研究基础上，这些研究表明Gli蛋白是Hedgehog信号通路的主要靶标，可以被加工成产生激活物或抑制物。然而，关于Gli功能的关键问题仍然没有答案。特别是，目前还不清楚它们的活性在多大程度上受辅助因素的控制，或者它们在表观遗传变化中扮演什么角色。由于Gli蛋白是广泛的转录调节蛋白，这些问题是至关重要的。 线虫为回答这些问题提供了一个理想的模型。它们只有一种Gli蛋白，TRA-1，与人类Gli蛋白有许多相似之处。然而，TRA-1控制性命运，并在自我生育中发挥核心作用。因此，在胚系中，它的激活和抑制功能之间的平衡使布里奇萨成为识别和评估辅助因子的理想选择。最后，布里奇萨线虫和线虫的解剖结构简单而完整，这使得研究发育过程中染色质调节的组织特异性效应成为可能。在其他动物身上进行类似的研究也很困难。 线虫遗传学和发育生物学的力量将简单地识别Gli辅助因子，并分析它们如何与TRA-1一起激活或抑制靶标。事实上，直接转录控制和表观遗传效应都可以在活体动物中进行研究。因此，这项建议有三个目标： 目的#1：明确TRA-1在线虫中的激活和抑制功能。 目的#2：确定已知的辅助因子如何与TRA-1亚型相互作用来调节靶基因。 目的#3：确定新的TRA-1辅助因子。 由于TRA-1是一个模型Gli蛋白，它的许多辅助因子和调节相互作用可能是保守的。因此，确定辅助因素并阐明它们如何与TRA-1一起工作，应该可以阐明人类的发育和疾病。此外，没有与人类共享的新的辅助因子可能会定义抗蠕虫药物的新靶点。由于防止成虫在人类宿主中繁殖是管理寄生线虫的关键，因此针对性别决定途径的这一部分的能力可能是无价的。最后，线虫是性别决定的顶级模型之一(正如《发育生物学》等教科书中的报道所表明的那样)，所以我们破译故事的核心部分是至关重要的。

Gli proteins constitute a vital but complex group of transcription factors. Humans have three, and mutations in them or errors in their regulation can cause developmental disorders or cancer. Our understanding of these proteins has rested on studies of their Drosophila ortholog Cubitus interruptus, which revealed that Gli proteins are a major target of the Hedgehog-signaling pathway, and can be processed to produce either activators or repressors. However, key questions about Gli function remain unanswered. In particular, it is not clear how much of their activity is controlled by co-factors, or what role they play in epigenetic changes. Since Gli proteins are broad transcriptional regulators, these questions are critical. Caenorhabditis nematodes provide an ideal model for answering these questions. They have a single Gli protein, TRA-1, that shares many similarities with human Gli proteins. However, TRA-1 controls sexual fates and plays a central role in self-fertility. As a result, the balance between its activating and repressing functions in the germ line makes C. briggsae ideal for identifying and evaluating co-factors. Finally, the anatomy of C. briggsae and C. elegans are simple and completely defined, which makes it feasible to study tissue-specific effects of chromatin regulation during development. Similar studies are difficult in other animals. The power of nematode genetics and developmental biology will simply the identification of Gli co-factors, and the analysis of how they work with TRA-1 to activate or repress targets. Indeed, direct transcriptional control and epigenetic effects can both be studied in living animals. Thus, this proposal has three aims: Aim #1: Define TRA-1 activator and repressor functions in Caenorhabditis nematodes. Aim #2: Determine how known co-factors interact with TRA-1 isoforms to regulate target genes. Aim #3: Identify new TRA-1 co-factors. Since TRA-1 is a model Gli protein, many of its co-factors and regulatory interactions are likely to be conserved. Thus, identifying co-factors and elucidating how they work with TRA-1 should illuminate human development and disease. In addition, novel co-factors that are not shared with humans could define new targets for antihelminthic drugs. Since preventing adult worms from reproducing in their human hosts is a critical for managing parasitic nematodes, the ability to target this part of the sex determination pathway could be invaluable. Finally, nematodes are one of the top models for sex determination (as shown by coverage in textbooks like Developmental Biology), so it is critical that we decipher the central part of the story.