In vivo repression of an erythroid-specific gene by distinct corepressor complexes.
To assess the mechanisms of repression of the erythroid-specific carbonic anhydrase II (CAII) locus we used chromatin immunoprecipitation and show that an NCoR-histone deacetylase (HDAC)3 complex is recruited by the nuclear receptor v-ErbA to the intronic HS2 enhancer turning it into a potent silencer. Furthermore we demonstrate that efficient CAII silencing requires binding of a MeCP2-targeted HDAC-containing corepressor complex to the hypermethylated CpG-island at the promoter. Activation of transcription by either AZAdC or thyroid hormone results in loss of one of the two corepressor complexes. Thyroid hormone further replaces the enhancer-bound NCoR-corepressor complex by the TRAP220 coactivator. Treatment with the HDAC inhibitor trichostatin A (TSA) causes activation of CAII transcription and histone H3 and H4 hyperacetylation at the enhancer, apparently without affecting binding of the two corepressor complexes. Unexpectedly, histone H3 and H4 at the fully repressed promoter are already hyperacetylated despite the close apposition of the MeCP2-targeted HDAC complex. Acetylation of histone H4, but not H3, at the promoter is moderately increased following TSA treatment. Our data suggest that the hyperacetylated but repressed CAII promoter is (partially) remodeled and primed for activation in v-ErbA-transformed cells.
Rietveld
Luc E G
LE
Department of Molecular Biology, NCMLS 191, University of Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Caldenhoven
Eric
E
Stunnenberg
Hendrik G
HG
D000107:Acetylation; D024402:Carbonic Anhydrase II / Q000235:genetics*; D002461:Cell Line, Transformed; D002868:Chromosomal Proteins, Non-Histone; D018899:CpG Islands; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2; D009687:Nuclear Proteins / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D018774:Oncogene Proteins v-erbA / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D015533:Transcriptional Activation; D014284:Triiodothyronine / Q000494:pharmacology; D000099186:Histone Deacetylase 3
D024402:Carbonic Anhydrase II; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D051783:Methyl-CpG-Binding Protein 2; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D018774:Oncogene Proteins v-erbA; D012097:Repressor Proteins; D014284:Triiodothyronine; D000099186:Histone Deacetylase 3; C497392:MECP2 protein, human; C539127:NCOR1 protein, human