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. PROJECT NARRATIVE 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.
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.
|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|
|Purcell, Daniel J; Khalid, Omar; Ou, Chen-Yin et al. (2012) Recruitment of coregulator G9a by Runx2 for selective enhancement or suppression of transcription. J Cell Biochem 113:2406-14|
|Won Jeong, Kwang; Chodankar, Rajas; Purcell, Daniel J et al. (2012) Gene-specific patterns of coregulator requirements by estrogen receptor-Ã½Ã½ in breast cancer cells. Mol Endocrinol 26:955-66|
|Lee, Young-Ho; Bedford, Mark T; Stallcup, Michael R (2011) Regulated recruitment of tumor suppressor BRCA1 to the p21 gene by coactivator methylation. Genes Dev 25:176-88|
|Lee, Young-Ho; Stallcup, Michael R (2011) Roles of protein arginine methylation in DNA damage signaling pathways is CARM1 a life-or-death decision point? Cell Cycle 10:1343-4|
|Ou, Chen-Yin; LaBonte, Melissa J; Manegold, Philipp C et al. (2011) A coactivator role of CARM1 in the dysregulation of Î²-catenin activity in colorectal cancer cell growth and gene expression. Mol Cancer Res 9:660-70|
|Obianyo, Obiamaka; Causey, Corey P; Osborne, Tanesha C et al. (2010) A chloroacetamidine-based inactivator of protein arginine methyltransferase 1: design, synthesis, and in vitro and in vivo evaluation. Chembiochem 11:1219-23|
|Lee, Young-Ho; Stallcup, Michael R (2009) Minireview: protein arginine methylation of nonhistone proteins in transcriptional regulation. Mol Endocrinol 23:425-33|
Showing the most recent 10 out of 11 publications