Reading and function of a histone code involved in targeting corepressor complexes for repression.
A central question in histone code theory is how various codes are recognized and utilized in vivo. Here we show that TBL1 and TBLR1, two WD-40 repeat proteins in the corepressor SMRT/N-CoR complexes, are functionally redundant and essential for transcriptional repression by unliganded thyroid hormone receptors (TR) but not essential ... for transcriptional activation by liganded TR. TBL1 and TBLR1 bind preferentially to hypoacetylated histones H2B and H4 in vitro and have a critical role in targeting the corepressor complexes to chromatin in vivo. We show that targeting SMRT/N-CoR complexes to the deiodinase 1 gene (D1) requires at least two interactions, one between unliganded TR and SMRT/N-CoR and the other between TBL1/TBLR1 and hypoacetylated histones. Neither interaction alone is sufficient for the stable association of the corepressor complexes with the D1 promoter. Our data support a feed-forward working model in which deacetylation exerted by initial unstable recruitment of SMRT/N-CoR complexes via their interaction with unliganded TR generates a histone code that serves to stabilize their own recruitment. Similarly, we find that targeting of the Sin3 complex to pericentric heterochromatin may also follow this model. Our studies provide an in vivo example that a histone code is not read independently but is recognized in the context of other interactions.
Mesh Terms:
Acetylation, Blotting, Western, Cell Nucleus, Chromatin, Chromatin Immunoprecipitation, Chromatography, Gel, Cloning, Molecular, Glutathione Transferase, Hela Cells, Heterochromatin, Histones, Humans, Immunoprecipitation, Iodide Peroxidase, Ligands, Lysine, Models, Biological, Nuclear Proteins, Plasmids, Promoter Regions, Genetic, Protein Binding, Protein Structure, Tertiary, RNA, Small Interfering, Receptors, Cytoplasmic and Nuclear, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Transcription, Genetic, Transcriptional Activation, Transducin
Acetylation, Blotting, Western, Cell Nucleus, Chromatin, Chromatin Immunoprecipitation, Chromatography, Gel, Cloning, Molecular, Glutathione Transferase, Hela Cells, Heterochromatin, Histones, Humans, Immunoprecipitation, Iodide Peroxidase, Ligands, Lysine, Models, Biological, Nuclear Proteins, Plasmids, Promoter Regions, Genetic, Protein Binding, Protein Structure, Tertiary, RNA, Small Interfering, Receptors, Cytoplasmic and Nuclear, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Transcription, Genetic, Transcriptional Activation, Transducin
Mol. Cell. Biol.
Date: Jan. 01, 2005
PubMed ID: 15601853
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