The long term objectives of this project are to define mechanisms of transcriptional regulation in metazoans, to understand how a regulatory factor specifies programs of gene expression as a function of developmental, cellular or physiological cues, and to decypher gene regulatory circuits. The general strategy is to identify in mammalian cells target genes that are directly regulated by members of the intracellular receptor (IR) superfamily, such as the glucocorticoid receptor. By comparing the regulatory machinery at subsets of those target genes, determinants of selective assembly and disassembly of regulatory complexes will be defined;in turn, the complexes will be probed to elucidate signaling and regulatory mechanisms.
The specific aims are to define key aspects of the structure, mechanisms, dynamics and combinatorial selectivities of IR regulatory complexes, and how they serve as nexus for integration of signaling pathways in regulatory networks. Four goals are envisioned: (1) define determinants of composition and architecture for assembly of IR regulatory complexes;(2) determine molecular mechanisms by which IR regulatory complexes modulate transcription;(3) determine how small molecule ligands specify functional surfaces of IRs;(4) determine mechanisms of disassembly of IR regulatory complexes. IRs have been implicated in a wide range of diseases and developmental disorders, including cancer, diabetes, osteoporosis, hypertension and inflammation, and IR ligands are the most heavily prescribed therapeutics. Thus, understanding the principles and mechanisms of IR action has important implications for health, and for detecting, treating and curing disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Sathyamoorthy, Neeraja
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Weikum, Emily R; Knuesel, Matthew T; Ortlund, Eric A et al. (2017) Glucocorticoid receptor control of transcription: precision and plasticity via allostery. Nat Rev Mol Cell Biol 18:159-174
Pack, Lindsey R; Yamamoto, Keith R; Fujimori, Danica Galoni? (2016) Opposing Chromatin Signals Direct and Regulate the Activity of Lysine Demethylase 4C (KDM4C). J Biol Chem 291:6060-70
Ward, Jordan D (2015) Rapid and precise engineering of the Caenorhabditis elegans genome with lethal mutation co-conversion and inactivation of NHEJ repair. Genetics 199:363-77
Zhang, Liangyu; Ward, Jordan D; Cheng, Ze et al. (2015) The auxin-inducible degradation (AID) system enables versatile conditional protein depletion in C. elegans. Development 142:4374-84
Ratnappan, Ramesh; Amrit, Francis R G; Chen, Shaw-Wen et al. (2014) Germline signals deploy NHR-49 to modulate fatty-acid ?-oxidation and desaturation in somatic tissues of C. elegans. PLoS Genet 10:e1004829
Schiller, Benjamin J; Chodankar, Rajas; Watson, Lisa C et al. (2014) Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes. Genome Biol 15:418
Chodankar, Rajas; Wu, Dai-Ying; Schiller, Benjamin J et al. (2014) Hic-5 is a transcription coregulator that acts before and/or after glucocorticoid receptor genome occupancy in a gene-selective manner. Proc Natl Acad Sci U S A 111:4007-12
Ward, Jordan D; Yamamoto, Keith R; Asahina, Masako (2014) SUMO as a nuclear hormone receptor effector: New insights into combinatorial transcriptional regulation. Worm 3:e29317
Ward, Jordan D; Mullaney, Brendan; Schiller, Benjamin J et al. (2014) Defects in the C. elegans acyl-CoA synthase, acs-3, and nuclear hormone receptor, nhr-25, cause sensitivity to distinct, but overlapping stresses. PLoS One 9:e92552
Ward, Jordan D; Bojanala, Nagagireesh; Bernal, Teresita et al. (2013) Sumoylated NHR-25/NR5A regulates cell fate during C. elegans vulval development. PLoS Genet 9:e1003992

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