MLL3/4-complexes in nuclear receptor-mediated metabolism

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DESCRIPTION (provided by applicant): This is a renewal proposal for the previous work, entitled "Regulation Code by Nuclear Receptor Coactivator ASC-2". This previous study's goal was to define the roles for ASC-2 and its steady-state complex ASCOM (for ASC-2-COMplex) in nuclear receptor (NR) transactivation. During the course of this study, we made the novel finding that ASCOM plays crucial roles in metabolism. This includes lipid and glucose homeostasis, two key areas which are important for the metabolic syndrome. Importantly, the metabolic transcriptional regulation that can lead to this rapidly growing pandemic remains unclear. Therefore, this exciting new possibility for ASCOM to be directly involved with the metabolic syndrome attests the strength of the current proposal. The potential innovativeness of this study is also evident from the fact that ASCOM contains enzymes, which can serve as new targets for developing drugs to treat the metabolic syndrome. The major hypothesis of this study is that ASCOM is a coactivator complex specialized for at least a subset of NRs involved with metabolism. Specifically, we will determine 1) the biochemical and molecular function of key constituents of ASCOM during NR transactivation, which is a continuation of the previous aims, and 2) the role for ASCOM in lipid and glucose metabolism, which represents a newly focused area of study based on the metabolic function of ASCOM. It is important to note that this is a well-integrated study, because the first part of the study is essential to understand the molecular basis for the metabolic function of ASCOM in the second part of the study. These two critical issues will be addressed in three specific aims, which utilize an ensemble of biochemical, cellular and genetic approaches. In Aim 1, we will define the molecular mechanisms by which ASCOM regulates NR transactivation. In Aim 2, we will define the hepatic roles for ASCOM in liver X receptor (LXR) transactivation. In Aim 3, we will define the hepatic function for ASCOM in farnesoid X receptor (FXR) transactivation. Overall, this study will help understand the molecular mechanisms by which NRs regulate transcription and control metabolism and energy homeostasis. PUBLIC HEALTH RELEVANCE: We found that ASCOM plays central roles in a complex network of metabolic gene regulation by nuclear receptors. Thus, this study of ASCOM will directly contribute to our understanding of metabolic control by nuclear receptors. Moreover, this study can be directly applied to designing proper strategies to fight against the metabolic syndrome, a growing pandemic, because ASCOM has two distinct classes of chemically amenable enzymes.