Development of neurons, such as those of the endocrine hypothalamus invoves regulation by the actions of nuclear receptors and by other classes of transcription factors, such as the Class III POU domain factors, as well as the actions of specific signaling molecules. The initial five years under this Merit Award have proven to be our most productive and innovative cycle under this Grant. We have contributed a series of discoveries concerning the molecular mechanisms by which nuclear receptors mediate gene repression and activation events and that have established a new paradigm concerning the molecular mechanisms of gene regulation. Our central theme in our laboratory under this grant has been to define the molecular mechanisms by which nuclear receptors, POU domain factors, and other classes of transcriptionfactors function via recruitment of corepressors and coactivators, and to define a role for these factors in establishing neuronal and other cellular phenotypes and in regulating function. We have identified novel molecular mechanisms that regulate tissue- and cell type-specific proliferation and activation, and defined roles for corepressors in these events. We will investigate the molecular basis of action of components of the TBLR1/TBL1/GPS2/ HDAC3 complexes, investigating the potential roles of GPS2 as an inhibitor of specific protein kinases, and the roles of site-specific phosphorylation of N-CoR/TBLR1 and TBL1 in the required recruitment of specific ubiquitin ligase 19S proteasome machinery using neuronal models. The relationship of these factors to the actin-related complexes that may detect nuclear localization and alterations in chromatin structure will be defined

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK039949-28
Application #
7738496
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sato, Sheryl M
Project Start
1982-08-01
Project End
2010-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
28
Fiscal Year
2010
Total Cost
$654,966
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Yang, Feng; Ma, Qi; Liu, Zhijie et al. (2017) Glucocorticoid Receptor:MegaTrans Switching Mediates the Repression of an ER?-Regulated Transcriptional Program. Mol Cell 66:321-331.e6
Gao, Xiaofei; Lee, Hsiang-Ying; Li, Wenbo et al. (2017) Thyroid hormone receptor beta and NCOA4 regulate terminal erythrocyte differentiation. Proc Natl Acad Sci U S A 114:10107-10112
Puc, Janusz; Aggarwal, Aneel K; Rosenfeld, Michael G (2017) Physiological functions of programmed DNA breaks in signal-induced transcription. Nat Rev Mol Cell Biol 18:471-476
Scully, Kathleen M; Skowronska-Krawczyk, Dorota; Krawczyk, Michal et al. (2016) Epithelial cell integrin ?1 is required for developmental angiogenesis in the pituitary gland. Proc Natl Acad Sci U S A 113:13408-13413
Puc, Janusz; Kozbial, Piotr; Li, Wenbo et al. (2015) Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160:367-80
Li, Wenbo; Hu, Yiren; Oh, Soohwan et al. (2015) Condensin I and II Complexes License Full Estrogen Receptor ?-Dependent Enhancer Activation. Mol Cell 59:188-202
Wang, Jianxun; Telese, Francesca; Tan, Yuliang et al. (2015) LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control. Nat Neurosci 18:1256-64
Telese, Francesca; Ma, Qi; Perez, Patricia Montilla et al. (2015) LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation. Neuron 86:696-710
Zhang, Feng; Tanasa, Bogdan; Merkurjev, Daria et al. (2015) Enhancer-bound LDB1 regulates a corticotrope promoter-pausing repression program. Proc Natl Acad Sci U S A 112:1380-5
Skowronska-Krawczyk, Dorota; Ma, Qi; Schwartz, Michal et al. (2014) Required enhancer-matrin-3 network interactions for a homeodomain transcription program. Nature 514:257-61

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