N-CoR-HDAC Corepressor Complexes: Roles in Transcriptional Regulation by Nuclear Hormone Receptors
Many nuclear hormone receptors (NHRs) actively repress the expression of their primary response genes through the recruitment of transcriptional corepressor complexes to regulated promoters. N-CoR and the highly related SMRT were originally isolated and c
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N-CoR-HDAC Corepressor Complexes: Roles in Transcriptional Regulation by Nuclear Hormone Receptors P. L. JON ES, Y.-B.SHI
Int roduct ion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 2 2. I 2.2
NHRs, Gene Regul at ion and Chromatin 239 The Metamorphosis Mod el . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 24 I Thyroid Hormon e Recept or and Chro matin
3 3.1 3.2
The N-CoR and SMRT Corepresso r Proteins . . . . . . . . . . . . . . . .. 244 245 Orga nizatio n and Functio nal Domains of N-CoR and SMRT 246 The N-Co RISMRT-H DAC Connec tion
4 4. I 4.1.2 4.1.3 4.2 4.2. 1
N-CoR and SMRT Corep resso r Com plexes . . . . . . . . . . . . . . . . . . 247 Core pressor Complexes Con ta ining N-CoR 248 Xenopus laevis Eggs Conta in Two Distinct N-CoR/H DAC Complexes 248 HeLa Cells Conta in Two Distinct N-CoR/HDAC Complexes 251 Multi ple HDACs Assoc iate wit h N-Co R In Vivo 254 Corepressor Complexes Containing SMRT . . . . . . . . . . . . . . . . . . 256 The SMRT/HDAC3/TBLI Complex in HeLa Cells 257
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Targe ting the N-CoR and SMRT Corepressor Complexes to NHRs . . . .. 258
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Sum ma ry
4.1.1
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References
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Abstract. Many nucle ar ho rmone receptors (NHRs) actively repress the expression of their primar y response genes through the recruitment of transcriptional corepressor comple xes to regulated promoters. N-CoR and the highly related SMRT were originally isolated and cha racterized by P. L. JO N ES Depar tme nt of Cell and Structural Biology, University of Illinoi s at Urban a-Champaign, BI07 CLSL,601 S. Goodwin Ave, Urbana, IL 61801, USA
e-mail:[email protected] Y.-B. SH I Unit on Molecular Morphogen esis, Nation al Institute of Child Health and Hum an Development , Nat ion al Ins titutes of Health, 9000 Rockville Pike, Bldg 18T Rm 106, Beth esd a, MD 20892, USA
e-mail: [email protected]
J.L. Workman (ed.), Protein Complexes that Modify Chromatin © Springer- Verlag Berlin Heidelberg 2003
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P. L. JONES and Y.-B. SHI
their ability to interact exclusively with the unliganded forms ofNHRs and confer transcriptional repression. Recently, both the N-CoR and SMRT corepressors have been found to exist in vivo in multiple, distinct macromolecular complexes. While these corepressor complexes differ in overall composition, a general theme is that they contain histone deacetylase enzymatic activity. Several of these complexes contain additional transcriptional corepressor proteins with functional ties to chromatin structure. Together, these data suggest that modulation of chromatin structure plays a central role in N-CoR mediated transcriptional repression from unliganded NHRs. 1
Introduction Many nuclear hormone receptors (NHRs) are able to activate as well as repress specific gene expression while bound to their same cis-acting element, dependent on the presence or absence of ligand (reviewed in McKENNA et al. 1999; URNOV and WOLFFE 2001). This observation led to the discovery in 1995 of a new fam
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