Regulatory Mechanisms in Hormonal and Transcriptional Signaling

Northwestern University At Chicago, Evanston IL

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Abstract

Nuclear receptors bind to hormones and vitamins and regulate the activity of hormone inducible genes which in turn influence a cascade of events that impact almost all physiologic pathways including cell differentiation, fat metabolism, energy homeostasis and reproduction. Nucleosomes, the building blocks of chromatin are DNAhistone complexes and play pivotal roles in regulating both transcriptional activation and repression. Consequently posttranslational nucleosome/histone modification and nucleosome remodeling are proposed to be critical for gene regulation. While the roles of chromatin modifying proteins such as histone acetyltransferases and histone deacetylases in regulation of hormone inducible genes are well documented, surprisingly very little is known about the role of chromatin remodeling proteins in regulating hormone/vitamin inducible genes. Additionally if and how hormone alters nucleosome positioning of hormone inducible genes is not well understood. We recently identified and characterized human ATP-utilizing chromatin assembly and remodeling factor 1 (hAcf1) as a critical regulator of hormone action and NR function. Our preliminary data enable us to propose hormone and Acf1 dependent nucleosome repositioning as a defining event in hormone action. We hypothesize that Acf1 plays critical roles in integrating hormone action and chromatin remodeling that defines the transcriptional output of NR target genes. To test this hypothesis, we will perform experiments under three specific aims that will determine the in depth mechanisms of action of Acf1 and hormone induced chromatin remodeling in NR function. In this proposal we will first analyze the innovative concept that Acf1 integrates hormone action to chromatin remodeling at target genes, which is a crucial event in both gene activation and repression. The proposal will also test the hypothesis that a novel role of hormone is to reposition nucleosome and /or to promote histone eviction/exchange. Our genome wide screen for Acf1 regulated genes (as determined by microarray) as well as its genome wide binding (as determined by ChIPSeq) adds additional innovative concepts in NR research. We will use state of the art molecular, biochemical as well as newly developed techniques such as microarray and genome-wide deep sequencing methods to address the specific aims. Since epigenomic control of hormone action and NR function is new and rapidly evolving concept, we believe our work which are highly innovative in nature will significantly advance the field forward. By making key links between chromatin remodeling events and NR biology our work should provide a better understanding of hormone action and facilitate development of novel drugs that targets chromatin remodelers in treatment of human diseases