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

智力价值：从过去十年的测序数据爆炸式增长中可以明显看出，我们与动物有大量的共同基因，既有类人猿的相似之处，又有蠕虫和苍蝇的惊人的不同之处。这些基因是如何被调控的，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发挥着关键作用，也是拥有如此相似基因的动物如此令人着迷的不同的原因之一。被称为转录因子的蛋白质通过帮助打开或关闭基因来调节它们。有趣的是，同样的蛋白质可以在一个组织中打开一个基因，在另一个组织中关闭。尽管对基因调控进行了几十年的研究，但我们仍然不太清楚这些蛋白质是如何表现出如此多样化的组织特异性活性的。这个项目将利用一种更简单的动物--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，三天内从卵发育成成虫，但拥有大量与人类相同的基因和转录因子。通过研究单个转录因子如何在三种不同的组织中发挥作用，特别是研究两种调控因子的影响，我们将深入了解组织特异性基因调控是如何发挥作用的。广泛的影响：该项目将与来自东欧的杰出女科学家浅娜雅子博士建立并保持合作，并培训来自少数族裔的学生，这些学生是一个特殊的本科生研究项目的一部分。山本教授还将利用他在这项拟议研究中的发现来拓宽和丰富他在加州大学旧金山分校生物调控机制研究生课程中的教学内容，并反过来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，山本教授将利用这些研究和教育机会和成果作为具体例子，以活跃和增强他的科学和公共政策努力，以及联邦一级的公共沟通和外联活动。

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.