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

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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.