The homeostatic regulation of bile acid (BA) signaling requires a complex network of nuclear receptors (NRs), but their coactivators that remodel chromatin and regulate gene transcription in response to BA signaling are poorly understood. Our discovery of the NR coactivator ASC-2 led to our subsequent purification of 'ASC-2- complex'(ASCOM), the first mammalian complex that contains the H3 lysine 4 methyltransferase (H3K4MT) MLL3 or its paralogue MLL4. Later, ASCOM has also been found to contain the H3-lysine 27-demethylase (H3K27DM) UTX. Trimethylated H3K4 and trimethylated H3K27 mark transcriptionally active and inactive chromatin, respectively. Thus, ASCOM contains two types of enzymes that are linked to transcriptional activation. Excitingly, we found that the major physiological function of ASCOM is to regulate metabolism under a variety of different conditions primarily attributed by the ability of ASC-2 to recruit ASCOM to multiple metabolic NRs, including PPAR?, LXRs, and FXR, the NR for BAs. In particular, we discovered that ASCOM functions as a critical coactivator for FXR in regulating BA synthesis. Consistently, one of the most salient phenotypes of our MLL3 mutant mice was a significant increase in BA levels, suggesting that MLL3-mediated H3K4MT activity of ASCOM is essential for maintaining BA homeostasis. Intriguingly, our MLL3 mutant mice also displayed favorable metabolic profiles, which we propose is via defects in the ability of ASCOM to antagonize signaling by Tgr5, the plasma membrane receptor for BAs. Tgr5 triggers a signaling pathway that leads to upregulation of 'the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase'(D2) and to enhance secretion of glucagon-like peptide-1 (GLP-1), an insulin secretagogue, thereby resulting in enhanced energy expenditure and improved glucose homeostasis. Our preliminary results suggest that ASCOM inhibits Tgr5 signaling not only through decreasing BA levels but also directly through the regulation of a gene encoding a key modifier of Tgr5 signaling, 'dipeptidyl peptidase-4'(Dpp4), which inactivates GLP-1. Together, these results support the central hypothesis of this study: ASCOM functions as a master coactivator of 'the homeostatic regulation of BA signaling'by controlling the expression of genes in multiple pathways that regulate BA metabolism and signaling. This renewal has two objectives: 1) We will test the mechanisms of action for ASCOM in NR transactivation (primarily for FXR and RAR) by using the discoveries made during the previous funding period. 2) By focusing specifically on the role of ASCOM in BA homeostasis, we will establish a new paradigm for understanding the diverse metabolic roles of ASCOM. This is a well-integrated study, as the first part of the study is critical to understand the molecular basis for the functio of ASCOM in BA homeostasis and signaling (the second part of the study). We will tackle these two issues in three specific aims, utilizing a combination of biochemical, cellular and genetic approaches. This study will help us to understand the molecular basis for how NRs regulate transcription and metabolism.

Public Health Relevance

The metabolic syndrome is rapidly becoming a pandemic in our society. To deal with this serious problem, we need to fully understand the molecular underpinnings for the metabolic syndrome. Here we wish to focus on a novel player in metabolic syndrome, named ASCOM (for ASC-2 complex), which contains two distinct types of enzymes that can be readily targeted for new drug development in treating diverse metabolic diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Margolis, Ronald N
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Oregon Health and Science University
Schools of Medicine
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