The long term objectives of this project are to understand metazoan transcriptional regulation, and mechanisms by which a regulatory factor can specify different programs of gene expression as a function of developmental or physiological cues. The general strategy of the proposed research is to analyze regulation by members of the intracellular receptor (IR) superfamily, which includes receptors for steroids, thyroid hormone, retinoids, and other small lipophilic ligands. Combinatorial regulation likely reflects the controlled assembly of multifactor regulatory complexes, whose components and functions are context-dependent. Thus, the assembly and functions of IR regulatory complexes in different contexts will be dissected mechanistically, in settings ranging from pure proteins to whole organisms.
The specific aims of the present study are to characterize the structure and activities of IR regulatory complexes under conditions in which the ligand (which defines a cell-specific context) or the response element (which defines a gene-specific context) are varied within the complexes. Four goals are envisioned: (1) determine how functionally distinct regulatory complexes are specified by ligands; (2) determine how gene-specific regulatory complexes and IR functions are specified by response elements; (3) determine the structure and significance of receptor interactions with Swi/Snf chromatin remodeling complexes; (4) investigate IR regulatory complex formation and function in the simple metazoan C. elegans. In these experiments, molecular genetic, biochemical and structural approaches will be used to identify functional surfaces and interacting factors that specify transcriptional activation, repression, composite regulation and synergy in vitro, in cells and in whole animals. IRs have been implicated in a wide range of diseases, including cancer, hypertension and inflammation, and IR ligands are widely used as therapeutics, diagnostics and chemopreventatives. Thus, understanding the principles and mechanisms of IR action has important implications for health, and for detecting, treating and curing disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA020535-27S1
Application #
6931383
Study Section
Molecular Biology Study Section (MBY)
Program Officer
Mietz, Judy
Project Start
1976-12-01
Project End
2005-01-31
Budget Start
2003-08-15
Budget End
2005-01-31
Support Year
27
Fiscal Year
2004
Total Cost
$111,763
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
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
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; 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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