Targeting of N-CoR and histone deacetylase 3 by the oncoprotein v-erbA yields a chromatin infrastructure-dependent transcriptional repression pathway.
Transcriptional repression by nuclear hormone receptors is thought to result from a unison of targeting chromatin modification and disabling the basal transcriptional machinery. We used Xenopus oocytes to compare silencing effected by the thyroid hormone receptor (TR) and its mutated version, the oncoprotein v-ErbA, on partly and fully chromatinized TR-responsive templates in vivo. Repression by v-ErbA was not as efficient as that mediated by TR, was significantly more sensitive to histone deacetylase (HDAC) inhibitor treatment and, unlike TR, v-ErbA required mature chromatin to effect repression. We find that both v-ErbA and TR can recruit the corepressor N-CoR, but, in contrast to existing models, show a concomitant enrichment for HDAC3 that occurs without an association with Sin3, HDAC1/RPD3, Mi-2 or HDAC5. We propose a requirement for chromatin infrastructure in N-CoR/HDAC3-effected repression and suggest that the inability of v-ErbA to silence on partly chromatinized templates may stem from its impaired capacity to interfere with basal transcriptional machinery function. In support of this notion, we find v-ErbA to be less competent than TR for binding to TFIIB in vitro and in vivo.
Sangamo Biosciences, Point Richmond Technology Centre, 501 Canal Boulevard, Suite A100, Richmond, CA 94804, USA.
F D
FD
Urnov
J
J
Yee
L
L
Sachs
T N
TN
Collingwood
A
A
Bauer
H
H
Beug
Y B
YB
Shi
A P
AP
Wolffe
D000251:Adenosine Triphosphatases; D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D002645:Chickens; D002843:Chromatin / Q000378:metabolism*; D004265:DNA Helicases; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D009687:Nuclear Proteins / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D018774:Oncogene Proteins v-erbA / Q000378:metabolism*; D009865:Oocytes; D011485:Protein Binding; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014982:Xenopus laevis
D001324:Autoantigens; C115323:CHD4 protein, human; D002843:Chromatin; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D018774:Oncogene Proteins v-erbA; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; C071731:SIN3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D000251:Adenosine Triphosphatases; D004265:DNA Helicases