Coregulator Codes of Transcriptional Regulation by Nuclear Receptors (2001)

hormone response element peroxisome proliferator-activated receptor thyroid hormone receptor estrogen receptor ligand binding domain nuclear receptor corepressor silencing mediator of retinoic acid and thyroid hormone receptor imitation SWI cAMP response element-binding protein CREB-binding protein histone acetyltransferase mitogen-activated protein histone deacetylase steroid receptor coactivator RAR interacting protein glucocorticoid receptor interacting protein T3R receptor associated protein vitamin receptor D interacting protein Members of the nuclear receptor superfamily directly activate or repress target genes by binding to hormone response elements (HREs)1 in promoter or enhancer regions, and by binding to other DNA sequence-specific activators and can inhibit the transcriptional activities of other classes of transcription factors by transrepression. Hormone response elements provide specificity to receptor homodimer heterodimer binding (reviewed in Ref. 2Bourguet W. Germain P. Gronemeyer H. Trends Pharm. Sci. 2000; 21: 381-388Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar). Nuclear receptor functions are directed by specific activation domains, referred to as activation function 1 (AF-1), which resides in the N terminus, and activation function 2 (AF-2), which resides in the C-terminal ligand binding domain (LBD) (reviewed in Ref. 1Glass C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar). Regulation of gene transcription by nuclear receptors requires the recruitment of proteins characterized as coregulators, with ligand-dependent exchange of corepressors for coactivators serving as the basic mechanism for switching gene repression to activation. In this review, we discuss biochemical and genetic studies suggesting that coregulatory complexes are differentially utilized in both a cell- and promoter-specific fashion to activate or repress gene transcription. These coregulatory components, themselves targets of diverse intracellular signaling pathways, provide a combinatorial code for tissue- and gene-specific responses, utilizing both enzymatic and platform assembly functions to mediate the actions of nuclear receptor genetic programs critical for developmental and homeostatic processes in metazoan organisms. A diverse group of proteins have emerged as potential coactivators for nuclear receptors. Ligand-dependent recruitment of coactivators is dependent on AF-2, which consists of a short conserved helical sequence within the C terminus of the LBD (2Bourguet W. Germain P. Gronemeyer H. Trends Pharm. Sci. 2000; 21: 381-388Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar). Biochemical and expression cloning approaches have been used to identify a large number of factors that interact with nuclear receptors in either a ligand-independent or a ligand-dependent manner and are often components of large multiprotein complexes. Many of these factors are capable of potentiating nuclear receptor activity in transient cotransfection assays. In addition, a distinct set of coactivators is associated with the AF-1 domain. As the number of potential coregulators clearly exceeds the capacity for direct interaction by a single receptor, the most plausible hypothesis is that transcriptional activation by nuclear receptors involves the actions of multiple factors. These factors act in a sequential and/or combinatorial manner to reorganize chromatin templates and to modify and recruit basal factors and RNA polymerase II (3Wu C. J. Biol. Chem. 1997; 272: 28171-28174Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Wade P.A. Wollfe A.P. Curr. Biol. 1999; 9: R221-R224Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). As chromatinized transcription units are “repressed” compared with naked DNA, a critical aspect of gene activation involves nucleosomal remodeling (reviewed in Refs. 3Wu C. J. Biol. Chem. 1997; 272: 28171-28174Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Wade P.A. Wollfe A.P. Curr. Biol. 1999; 9: R221-R224Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 5Struhl K. Cell. 1999; 98: 1-4Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar). Two general classes of chromatin remodeling factors that appear to play critical roles in transcriptional activation by nuclear receptors have been identified. These are ATP-dependent nucleosome remodeling complexes and factors that contain histone acetyltransferase activity. The yeast SWI·SNF complex facilitates the binding of sequence-specific transcription factors to nucleosomal DNA and can cause local changes in chromatin structure in an ATP-dependent manner (3Wu C. J. Biol. 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Kouzarides T. Nature. 1996; 384: 641-643Crossref PubMed Scopus (1549) Google Scholar, 11Ogryzko V.V. Schiltz R.L. Russanova V. Howard B.H. Nakatani Y. Cell. 1996; 87: 953-959Abstract Full Text Full Text PDF PubMed Scopus (2448) Google Scholar, 12Grant P.A. Duggan L. Cote J. Roberts S.M. Brownell J.E. Candau R. Ohba R. Owen-Hughes T. Allis C.D. Winston F. Berger S.L. Workman J.L. Genes Dev. 1997; 11: 1640-1650Crossref PubMed Scopus (897) Google Scholar). Mammalian homologues of Drosophila SWI2/SNF2 such as BRG1/hBrm function as components of large multiprotein complexes. Transfection of ATPase-defective alleles of either Brg1 orhBrm into several mammalian cell lines leads to a significant decrease in the ability of several nuclear receptors to activate transcription (3Wu C. J. Biol. Chem. 1997; 272: 28171-28174Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 4Wade P.A. Wollfe A.P. Curr. Biol. 1999; 9: R221-R224Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 5Struhl K. Cell. 1999; 98: 1-4Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar, 6Pazin M.J. Kadonaga J.T. Cell. 1997; 88: 737-740Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). Remodeling complexes containing ISWI (imitation SWI) may also be involved in nuclear receptor function (7Pazin M.J. Kadonaga J.T. Cell. 1997; 89: 325-328Abstract Full Text Full Text PDF PubMed Scopus (773) Google Scholar, 8Mizzen C.A. Yang X.-J. Kokubo T. Brownell J.E. Bannister A.J. Owen-Hughes T. Workman J. Wang L. Berger S.L. Kouzarides T. Nakatani Y. Allis C.D. Cell. 1996; 87: 1261-1270Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar, 9Ogryzko V.V. Kotani T. Zhang R.L. Howard S.T. Yang X.J. Howard B.H. Qin J. Nakatani Y. Cell. 1998; 94: 35-44Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar, 10Bannister A.J. Kouzarides T. Nature. 1996; 384: 641-643Crossref PubMed Scopus (1549) Google Scholar, 11Ogryzko V.V. Schiltz R.L. Russanova V. Howard B.H. Nakatani Y. Cell. 1996; 87: 953-959Abstract Full Text Full Text PDF PubMed Scopus (2448) Google Scholar). Rates of gene transcription roughly correlate with the degree of histone acetylation, with hyperacetylated regions of the genome appearing to be more actively transcribed than hypoacetylated regions (reviewed in Ref. 7Pazin M.J. Kadonaga J.T. Cell. 1997; 89: 325-328Abstract Full Text Full Text PDF PubMed Scopus (773) Google Scholar). The specific recruitment of a complex with histone acetyltransferase activity to a promoter may play a critical role in overcoming repressive effects of chromatin structure on transcription (4Wade P.A. Wollfe A.P. Curr. Biol. 1999; 9: R221-R224Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 5Struhl K. Cell. 1999; 98: 1-4Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar, 6Pazin M.J. Kadonaga J.T. Cell. 1997; 88: 737-740Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 7Pazin M.J. Kadonaga J.T. Cell. 1997; 89: 325-328Abstract Full Text Full Text PDF PubMed Scopus (773) Google Scholar). This concept was further supported by the subsequent finding that the mammalian Gcn5 orthologues, including p/CAF, CREB-binding protein (CBP), adenovirus E1A-binding protein p300, and TAFII250, each possess intrinsic histone acetyltransferase (HAT) activity (7Pazin M.J. Kadonaga J.T. Cell. 1997; 89: 325-328Abstract Full Text Full Text PDF PubMed Scopus (773) Google Scholar, 8Mizzen C.A. Yang X.-J. Kokubo T. Brownell J.E. Bannister A.J. Owen-Hughes T. Workman J. Wang L. Berger S.L. Kouzarides T. Nakatani Y. Allis C.D. Cell. 1996; 87: 1261-1270Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar, 9Ogryzko V.V. Kotani T. Zhang R.L. Howard S.T. Yang X.J. Howard B.H. Qin J. Nakatani Y. Cell. 1998; 94: 35-44Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar, 10Bannister A.J. Kouzarides T. Nature. 1996; 384: 641-643Crossref PubMed Scopus (1549) Google Scholar, 11Ogryzko V.V. Schiltz R.L. Russanova V. Howard B.H. Nakatani Y. Cell. 1996; 87: 953-959Abstract Full Text Full Text PDF PubMed Scopus (2448) Google Scholar). Conversely, the discovery that a mammalian histone deacetylase (HDAC) was a homologue of the yeast corepressor, RPD3 (13Taunton J. Hassig C.A. Schreiber S.L. Science. 1996; 272: 408-411Crossref PubMed Scopus (1569) Google Scholar), gave rise to the hypothesis that regulated activation events might involve the exchange of complexes containing histone deacetylase functions with those containing histone acetyltransferase activity (Fig. 1). It appears that in most cases the acetyltransferases are not directly recruited to nuclear receptors but associate with other coactivators that exhibit higher affinity for the liganded receptor. The acetyltransferase functions of factors such as CBP/p300 are directly required for enhanced transcription on chromatinized templates (14Kraus W. Manning E. Kadonaga J. Mol. Cell Biol. 1999; 19: 8123-8135Crossref PubMed Scopus (203) Google Scholar). A large number of proteins that are recruited in a ligand-dependent fashion have the capacity to enhance transcriptional activation by transient transfection. Several insights into the mechanisms by which coactivator complexes are recruited to nuclear receptors in a ligand-dependent manner have been provided by the initial identification of the p160 family of nuclear receptor coactivators, referred to as SRC-1/NCOA1, TIF2/GRIP1, and p/CIP/A1B1/ACTR/RAC/TRAM-1 (reviewed in Ref. 15McKenna N.J. Lanz R.B. O'Malley B.W. Endocr. Rev. 1999; 20: 321-344Crossref PubMed Scopus (1669) Google Scholar). The p160 factors consist of three members that exhibit a common domain structure, illustrated in Fig. 1. The central conserved domain mediates ligand-dependent interactions with the nuclear receptor LBD, whereas the conserved C-terminal transcriptional activation domains mediate interactions with either CBP/p300 or protein-arginine methyltransferase (16Chen D. Ma H. Hong H. Koh S.S. Huang S.-M. Schurter B.T. Aswad D.W. Stallcup M.R. Science. 1999; 284: 2174-2176Crossref PubMed Scopus (1019) Google Scholar, 17Koh S. Chen D. Lee Y. Stallcup M. J. Biol. Chem. 2001; 276: 1089-1098Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar). Based on the presence of three regulatory domains, members of the p160 family have been suggested to function as coactivators, at least in part, by serving as adapter molecules that recruit CBP and/or p300 complexes to promoter-bound nuclear receptors in a ligand-dependent manner (18Kurokawa R. Kalafus D. Ogliastro M.-H. Kioussi C. Xu L. Torchia J. Rosenfeld M.G. Glass C.K. Science. 1998; 279: 700-703Crossref PubMed Scopus (199) Google Scholar, 19Torchia J. Rose D.W. Inostroza J. Kamei Y. Westin S. Glass C.K. Rosenfeld M.G. Nature. 1997; 387: 677-684Crossref PubMed Scopus (1112) Google Scholar). Biochemical studies have also demonstrated strong ligand-dependent interactions between nuclear receptors and p140 factors, probably representing the coregulator RIP140, which results in a reproductive defect in female mice on gene deletion (20White R. Leonaardsson G. Roswell G. Jacobs I. Milligan S. Parker M. Nat. Med. 2000; 6: 1368-1374Crossref PubMed Scopus (165) Google Scholar). Analysis of the nuclear receptor interaction domain of the p160 family led to the identification of three repeated motifs with a consensus sequence LXXLL in which L represents leucine andX represents any amino acid. The LXXLL motif has been found to be necessary and sufficient for ligand-dependent interactions with the nuclear receptor ligand binding domain (19Torchia J. Rose D.W. 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Structural studies of the PPARγ, ER, and T3R ligand binding domains complexed to fragments of the p160 nuclear receptor interaction domains revealed that these motifs form short α helices (22Nolte R.T. Wisely G.B. Westin S. Cobb J.E. Lambert M.H. Kurokawa R. Rosenfeld M.G. Willson T.M. Glass C.K. Milburn M.V. Nature. 1998; 395: 137-143Crossref PubMed Scopus (1714) Google Scholar, 23Feng W. Ribeiro R.C.J. Wagner R.L. Nguyen H. Apriletti J.W. Fletterick R.J. Baxter J.D. Kushner P.J. West B.L. Science. 1998; 280: 1747-1749Crossref PubMed Scopus (520) Google Scholar, 24Darimont B.D. Wagner R.L. Apriletti J.W. Stallcup M.R. Kushner P.J. Baxter J.D. Fletterick R.J. Yamamoto K.R. Genes Dev. 1998; 12: 3343-3356Crossref PubMed Scopus (834) Google Scholar, 25Shiau A.K. Barstad D. Loria P.M. Cheng L. Kushner P.J. Agard D.A. Greene G.L. Cell. 1998; 95: 927-937Abstract Full Text Full Text PDF PubMed Scopus (2304) Google Scholar), with multiple LXXLL motifs within a single coactivator mediating cooperative interactions with nuclear receptor dimers or heterodimers. The LXXLL helix is oriented and positioned at each end by a “charge-clamp” consisting of a conserved lysine in helix 3 of the ligand binding domain and a conserved glutamate in the AF-2 helix. These residues grip the LXXLL helix so that the internal leucine residues can pack into a hydrophobic pocket in the receptor C terminus. Most nuclear receptor coactivators have proved to contain functionally important LXXLL helices, with additional residues contributing to binding specificity (e.g. Refs. 26McInerney E.M. Rose D.W. Flynn S.E. Westin S. Mullen T.-M. Krones A. Inostroza J. Torchia J. Nolte R.T. Assa-Munt N. Milburn M.V. Glass C.K. Rosenfeld M.G. Genes Dev. 1998; 12: 3357-3368Crossref PubMed Scopus (531) Google Scholar and 27Heery D. Hoare S. J. Biol. Chem. 2001; 276: 6695-6702Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). Furthermore, these contacts are sensitive to conformational changes induced by structurally distinct ligands. Many additional factors have been demonstrated to enhance nuclear receptor activity in functional assays, suggesting that they may serve as nuclear receptor coregulators (reviewed in Ref. 1Glass C.K. Rosenfeld M.G. Genes Dev. 2000; 14: 121-141Crossref PubMed Google Scholar). Biochemical studies and protein-protein interaction screens suggest that many of these proteins function as components of large multiprotein complexes and that additional enzymatic activities may be important for their function. For example, the p160 protein GRIP1 can associate with arginine methyltransferase 1 (CARM1), which potentiates ligand-dependent transcription by several nuclear receptors (16Chen D. Ma H. Hong H. Koh S.S. Huang S.-M. Schurter B.T. Aswad D.W. Stallcup M.R. Science. 1999; 284: 2174-2176Crossref PubMed Scopus (1019) Google Scholar). PRMTI, a second arginine methyltransferase to also functions as a nuclear receptor coactivator S. Chen D. Lee Y. Stallcup M. J. Biol. Chem. 2001; 276: 1089-1098Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar). The CBP/p300 coactivators can recruit additional factors with such as the complexes V.V. Schiltz R.L. Russanova V. Howard B.H. Nakatani Y. Cell. 1996; 87: 953-959Abstract Full Text Full Text PDF PubMed Scopus (2448) Google Scholar, R. Kalafus D. Ogliastro M.-H. Kioussi C. Xu L. Torchia J. Rosenfeld M.G. Glass C.K. Science. 1998; 279: 700-703Crossref PubMed Scopus (199) Google Scholar). The and of the recruited complexes may distinct acetyltransferases are required by transcription factors on specific gene targets E. Torchia J. Rose D.W. Xu L. Kurokawa R. E.M. Mullen T.M. Glass C.K. Rosenfeld M.G. Science. 1998; 279: PubMed Scopus Google Scholar). 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