Nuclear receptors (NRs) and other DNA-binding transcription factors regulate transcription of their target genes by recruiting coregulator proteins to the promoter of the target genes. Many coregulators can assist NRs as either coactivators or corepressors, depending on the regulatory context of the promoter. However, the mechanisms that govern whether a specific coregulator functions as coactivator or corepressor is unknown and will be a central focus of this application. Transcriptional repression involves recruitment of corepressor complexes which often include enzymes that deacetylate and make repressive methylation marks on histones. In particular, di- and trimethylation of lysine 9 of histone H3 (H3 K9) in gene promoters has been associated with gene repression. Knock-out mouse studies of the euchromatin-associated H3 K9 methyltransferases G9a and GLP indicated that these two enzymes are responsible for the majority of mono- and demethylation of H3 K9 in cells. The knock-out mouse results plus additional biochemical studies indicate that G9a and GLP function as heterodimer partners for at least some of their functions. G9a is also associated with corepressor complexes that mediate the effects of several repressive transcription factors. G9a and GLP can also function as coactivators for NRs, suggesting that G9a may play a critical role as a regulatory switch between activation and repression of transcription, depending on the regulatory context on a particular promoter. The goal of this project is to understand the mechanisms of coactivator and corepressor function by G9a and GLP. The central hypothesis is that specific protein- protein interactions determine whether G9a and GLP function as coactivators or corepressors on a given promoter. Among other protein-protein interactions, the ability of G9a and GLP to bind preferentially to histone H3 that is dimethylated at lysine 9 (recently discovered in this laboratory) will be investigated for its role in coregulator function. In addition, common, distinct, and complementary aspects of G9a and GLP function will be defined. Toward that end, the domains and specific protein- protein interactions of the domains of G9a and GLP which are important for their functions as coactivators and corepressors will be determined. Analyses will be performed on both transiently transfected reporter genes and endogenous target genes of G9a and GLP. These studies will thus significantly extend our understanding of the specific contributions of coregulators and histone modifications to transcriptional regulation of genes. In addition, since NRs play many critical roles in normal and pathological regulation of endocrine and metabolic physiology, the proposed studies will provide new knowledge that has important implications for human health.

Public Health Relevance

The proposed project will extend our knowledge of how a variety of hormones regulate the activities of specific genes and thereby control important physiological processes such as sexual development, response to stress, and glucose and fatty acid metabolism. The same hormones also play important roles in the onset, progression, and treatment of many diseases, including cancer, diabetes, and heart disease.

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 #
4R37DK055274-18
Application #
8969676
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Silva, Corinne M
Project Start
1999-01-15
Project End
2017-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
18
Fiscal Year
2016
Total Cost
$492,626
Indirect Cost
$194,065
Name
University of Southern California
Department
Biochemistry
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Jin, Ming Li; Kim, Young Woong; Jin, Hong Lan et al. (2018) Aberrant expression of SETD1A promotes survival and migration of estrogen receptor ?-positive breast cancer cells. Int J Cancer 143:2871-2883
Poulard, Coralie; Baulu, Estelle; Lee, Brian H et al. (2018) Increasing G9a automethylation sensitizes B acute lymphoblastic leukemia cells to glucocorticoid-induced death. Cell Death Dis 9:1038
Lee, Brian H; Stallcup, Michael R (2018) Different chromatin and DNA sequence characteristics define glucocorticoid receptor binding sites that are blocked or not blocked by coregulator Hic-5. PLoS One 13:e0196965
Poulard, Coralie; Bittencourt, Danielle; Wu, Dai-Ying et al. (2017) A post-translational modification switch controls coactivator function of histone methyltransferases G9a and GLP. EMBO Rep 18:1442-1459
Lee, Brian H; Stallcup, Michael R (2017) Glucocorticoid receptor binding to chromatin is selectively controlled by the coregulator Hic-5 and chromatin remodeling enzymes. J Biol Chem 292:9320-9334
Poulard, Coralie; Corbo, Laura; Le Romancer, Muriel (2016) Protein arginine methylation/demethylation and cancer. Oncotarget 7:67532-67550
Chodankar, Rajas; Wu, Dai-Ying; Gerke, Daniel S et al. (2015) Selective coregulator function and restriction of steroid receptor chromatin occupancy by Hic-5. Mol Endocrinol 29:716-29
Bittencourt, Danielle; Lee, Brian H; Gao, Lu et al. (2014) Role of distinct surfaces of the G9a ankyrin repeat domain in histone and DNA methylation during embryonic stem cell self-renewal and differentiation. Epigenetics Chromatin 7:27
Bittencourt, Danielle; Wu, Dai-Ying; Jeong, Kwang Won et al. (2012) G9a functions as a molecular scaffold for assembly of transcriptional coactivators on a subset of glucocorticoid receptor target genes. Proc Natl Acad Sci U S A 109:19673-8
Won Jeong, Kwang; Chodankar, Rajas; Purcell, Daniel J et al. (2012) Gene-specific patterns of coregulator requirements by estrogen receptor-? in breast cancer cells. Mol Endocrinol 26:955-66

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