Impact of sumoylation and Wnt/beta-catenin signaling on nuclear receptor-regulated tissue-specific transcription

智力优势：从过去十年测序数据的爆炸式增长来看，很明显，我们与类人猿等相似的动物有着大量的共同基因，而与蠕虫和苍蝇等截然不同的基因。这些基因是如何被调节的，以及它们何时何地被关闭和打开，在动物的正常发育、对环境压力和波动的反应中起着至关重要的作用，也是使基因如此相似的动物如此不同的部分原因。被称为转录因子的蛋白质通过帮助开启或关闭基因来调节基因。有趣的是，同样的蛋白质可以在一个组织中开启一个基因，在另一个组织中关闭一个基因。尽管对基因调控进行了数十年的研究，但我们仍然对这些蛋白质如何表现出如此多样化的组织特异性活性没有深刻的了解。这个项目将利用一种更简单的动物——秀丽隐杆线虫来探索这种生物学。这种蠕虫只有1毫米长，由959个细胞组成，在3天内从卵变成成虫，但却有大量与人类相同的基因和转录因子。通过研究单一转录因子如何在三种不同的组织中发挥作用，特别是研究两种调节因子的影响，将深入了解组织特异性基因调控的作用机制。更广泛的影响：该项目将与来自东欧的杰出女科学家Asahina Masako博士建立并维持合作关系，并培训来自代表性不足的少数民族的学生，这些学生是一个特殊的本科研究项目的一部分。山本教授还将利用他的研究成果来拓宽和丰富他在UCSF生物调控机制研究生课程的教学，反过来，他将利用该课程的范围和学生的意见来为我们的研究提供信息。最后，山本教授将以这些研究和教育机会和成果为具体例子，为他的科学和公共政策工作以及联邦层面的公共沟通和外展活动注入活力和力量。

Intellectual merit: From the explosion of sequencing data over the last decade it is apparent that we have a significant number of genes in common with animals as similar as apes and as strikingly different as worms and flies. How these genes are regulated, and when and where they are turned off and on, play a critical role in proper animal development, response to environmental stress and fluctuation, and are part of what makes animals with such similar genes so mesmerizingly different. Proteins called transcription factors regulate genes by helping turn them on or off. Intriguingly, the same protein can turn a single gene on in one tissue and off in another. Despite decades of research on gene regulation we still do not have a strong understanding of how these proteins can exhibit such diverse, tissue-specific activity. This project will harness a simpler animal, the worm C. elegans, to explore this biology. The worm is only 1 mm long, consisting of 959 cells, and goes from egg to adult in three days, yet has a vast number of genes and transcription factors in common with humans. By studying how a single transcription factor works in three different tissues, in particular studying the influence of two regulatory factors, insight will be gained into how tissue-specific gene regulation works.Broader impacts: This project will establish and sustain a collaboration with an outstanding woman scientist from eastern Europe, Dr. Masako Asahina, and to train students from underrepresented minorities who are part of a special undergraduate research program. Professor Yamamoto shall also use his findings from this proposed research to broaden and enrich his teaching in a UCSF graduate course on Biological Regulatory Mechanisms, and in turn, will use the scope of that course and input from its students to inform our research. Finally, Professor Yamamoto will use these research and educational opportunities and outcomes as specific examples to enliven and empower his science and public policy efforts, and public communication and outreach activities at the federal level.