Nuclear hormone receptors play key roles in homeostasis and energy metabolism through their action, as gene-specific transcription factors, in metabolic tissues. Their function on specific target genes is highly dependent upon interactions with cofactors (notably the 30-subunit Mediator complex) that interface directly with the general transcription machinery and with cofactors that act indirectly to effect histone modifications (epigenetic marks) of the chromatin template. These cofactors add an important level of gene regulation, and this proposal seeks to detail biochemical mechanisms by which nuclear receptors (including PPAR?, TR? and ERR?) and key interacting cofactors regulate genes important for white adipocyte differentiation and function (fat storage), brown fat differentiation and function (energy dissipation through adaptive thermogenesis) and muscle function. The cofactors of special interest include the primary receptor-interacting subunit of th Mediator (MED1), factors that may provide alternative or redundant pathways for Mediator recruitment, the brown fat differentiation factor PRDM16, the inducible PGC-1? that is important for thermogenesis in brown fat, corepressors (such as RIP140) that necessitate opposing coactivator functions, histone modifying factors such as the activating p300 acetyl- and SET1/MLL methyl-transferases, and other DNA-binding regulatory factors (C/EBPs) that act synergistically with PPAR?. The mechanism of action and physiological functions of these factors on key target genes will be studied by several complementary approaches. First, we will use cell-free systems reconstituted with purified factors and DNA templates to detail mechanisms of cofactors that facilitate direct activation or repression of the general transcriptio machinery, with special emphasis on Mediator recruitment by MED1 versus other cofactors. Second, we will use cell-free systems reconstituted with purified factors and chromatin templates to detail (i) mechanisms of cofactors that directly or indirectly (as bridging proteins) effect covalent histone modifications and (ii) functions of these modifications through recognition by other effectors. Third, we will investigate the in vivo gene/tissue-specific functions of nuclea receptor coactivators during adipogenesis and adaptive thermogenesis through the generation and analysis of conditional knockout and mutant knockin mice, with emphasis on the MED1 subunit that is conditionally required for high level nuclear receptor function and whose mutation results in mice with improved glucose tolerance and insulin sensitivity as well as resistance to diet induced obesity. Fourth, through further mouse genetic and in vitro assays, we will investigate the molecular basis for the dramatic, metabolically favorable phenotype (induction of the thermogenic UCP1 and slow-twitch Type I myofiber genes;increased insulin sensitivity/glucose tolerance and resistance to diet-induced obesity) in skeletal muscle-specific Med1 knockout mice. By identification of new factors and mechanisms, and thus of novel therapeutic targets, these studies will have important implications for the control of obesity and muscle dystrophy.

Public Health Relevance

Obesity and Type II diabetes represent worldwide health problems and result from imbalances in homeostasis and energy metabolism in metabolic tissues such as fat and muscle. The present proposal seeks to understand the molecular basis for the regulation, by nuclear hormone receptors and associated cofactors, of genes that regulate the differentiation and function of white fat (involved in energy storage), brown fat (involved in energy dissipation and newly recognized as important metabolic tissue in adult humans) and muscle. The results will have important implications for possible therapeutic approaches to these and other health problems.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Margolis, Ronald N
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Rockefeller University
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New York
United States
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Minsky, Neri; Roeder, Robert G (2017) Control of Secreted Protein Gene Expression and the Mammalian Secretome by the Metabolic Regulator PGC-1?. J Biol Chem 292:43-50
Wang, Shu-Ping; Tang, Zhanyun; Chen, Chun-Wei et al. (2017) A UTX-MLL4-p300 Transcriptional Regulatory Network Coordinately Shapes Active Enhancer Landscapes for Eliciting Transcription. Mol Cell 67:308-321.e6
Josefowicz, Steven Z; Shimada, Miho; Armache, Anja et al. (2016) Chromatin Kinases Act on Transcription Factors and Histone Tails in Regulation of Inducible Transcription. Mol Cell 64:347-361
Xie, Zhongyu; Zhang, Di; Chung, Dongjun et al. (2016) Metabolic Regulation of Gene Expression by Histone Lysine ?-Hydroxybutyrylation. Mol Cell 62:194-206
Yao, Xiao; Tang, Zhanyun; Fu, Xing et al. (2015) The Mediator subunit MED23 couples H2B mono-ubiquitination to transcriptional control and cell fate determination. EMBO J 34:2885-902
Sabari, Benjamin R; Tang, Zhanyun; Huang, He et al. (2015) Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol Cell 58:203-15
Iida, Satoshi; Chen, Wei; Nakadai, Tomoyoshi et al. (2015) PRDM16 enhances nuclear receptor-dependent transcription of the brown fat-specific Ucp1 gene through interactions with Mediator subunit MED1. Genes Dev 29:308-21
Holt, Matthew T; David, Yael; Pollock, Sam et al. (2015) Identification of a functional hotspot on ubiquitin required for stimulation of methyltransferase activity on chromatin. Proc Natl Acad Sci U S A 112:10365-70
Minsky, Neri; Roeder, Robert G (2015) Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1?. Proc Natl Acad Sci U S A 112:E5669-78
Mizuta, Shumpei; Minami, Tomoya; Fujita, Haruka et al. (2014) CCAR1/CoCoA pair-mediated recruitment of the Mediator defines a novel pathway for GATA1 function. Genes Cells 19:28-51

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