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.
Yoon
Ho-Geun
HG
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Choi
Youngsok
Y
Cole
Philip A
PA
Wong
Jiemin
J
D000107:Acetylation; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D002850:Chromatography, Gel; D003001:Cloning, Molecular; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006570:Heterochromatin / Q000737:chemistry; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D007453:Iodide Peroxidase / Q000235:genetics; D008024:Ligands; D008239:Lysine / Q000737:chemistry; D008954:Models, Biological; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015293:Transducin / Q000737:chemistry / Q000378:metabolism*
D002843:Chromatin; D006570:Heterochromatin; D006657:Histones; D008024:Ligands; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C119542:TBL1X protein, human; C473691:TBL1XR1 protein, human; D007453:Iodide Peroxidase; D005982:Glutathione Transferase; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D015293:Transducin; D008239:Lysine