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.
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.
|Roh, Jae-Il; Cheong, Cheolho; Sung, Young Hoon et al. (2014) Perturbation of NCOA6 leads to dilated cardiomyopathy. Cell Rep 8:991-8|
|Lee, Sunjae; Lee, KiYoung; Yoon, Seyeol et al. (2014) Anomalies in network bridges involved in bile Acid metabolism predict outcomes of colorectal cancer patients. PLoS One 9:e107925|
|Cho, Hyong-Ho; Cargnin, Francesca; Kim, Yujin et al. (2014) Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes. PLoS Genet 10:e1004280|
|Kim, Sun-Gyun; Lee, Bora; Kim, Dae-Hwan et al. (2013) Control of energy balance by hypothalamic gene circuitry involving two nuclear receptors, neuron-derived orphan receptor 1 and glucocorticoid receptor. Mol Cell Biol 33:3826-34|
|Lee, Seunghee; Shen, Rongkun; Cho, Hyong-Ho et al. (2013) STAT3 promotes motor neuron differentiation by collaborating with motor neuron-specific LIM complex. Proc Natl Acad Sci U S A 110:11445-50|
|Lee, Bora; Kim, Sun-Gyun; Kim, Juhee et al. (2013) Brain-specific homeobox factor as a target selector for glucocorticoid receptor in energy balance. Mol Cell Biol 33:2650-8|
|Lee, Seunghee; Cuvillier, James M; Lee, Bora et al. (2012) Fusion protein Isl1-Lhx3 specifies motor neuron fate by inducing motor neuron genes and concomitantly suppressing the interneuron programs. Proc Natl Acad Sci U S A 109:3383-8|
|Lee, Seunghee; Lee, Jae W; Lee, Soo-Kyung (2012) UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program. Dev Cell 22:25-37|
|Kim, Dae-Hwan; Kim, Juhee; Lee, Jae W (2011) Requirement for MLL3 in p53 regulation of hepatic expression of small heterodimer partner and bile acid homeostasis. Mol Endocrinol 25:2076-83|
|Kim, Dae-Hwan; Lee, Jae W (2011) Tumor suppressor p53 regulates bile acid homeostasis via small heterodimer partner. Proc Natl Acad Sci U S A 108:12266-70|
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