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Comments on Brooks, Alison et al. (2009) International Worm Meeting "Dissecting the structure-function relationship of NHR-49 through mutagenesis." (0)
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Brooks, Alison, & van Gilst, Marc (2009). Dissecting the structure-function relationship of NHR-49 through mutagenesis presented in International Worm Meeting. Unpublished information; cite only with author permission.
Nuclear receptors are a family of transcription factors that regulate a wide variety of gene sets. HNF-4a is a mammalian nuclear receptor that regulates expression of genes involved in development and lipid and glucose metabolism. Its targets have also been implicated in multiple cancers and diabetes. Like all nuclear receptors, HNF-4a exerts its control by coordinating the effects of ligands, coregulators, and specific response elements through their binding to distinct conserved domains. Because of its importance in basic metabolic function, its role in disease, and the potential to dissect its function based on subdomain, HNF-4a is an excellent target for pharmacologically-mediated selective modulation. However, the role of each domain in transcriptional regulation must be better understood before this may be accomplished. To this end, I propose to focus my efforts on elucidating the structure-function relationship of the C. elegans homolog, NHR-49, via site-directed mutagenesis. Working with nematodes will allow me to easily create a large panel of domain-specific mutants and test their in vivo effects. Furthermore, I will use the tractability of forward genetics in worms to look for constitutively active NHR-49 mutants to test my hypothesis that selective modulation of targets is possible.