Trichostatin A reduces hormone-induced transcription of the MMTV promoter and has pleiotropic effects on its chromatin structure.
The deacetylase inhibitor trichostatin A (TSA) has long been used to study the relationship between gene transcription and the acetylation status of chromatin. We have used Xenopus laevis oocytes to study the effects of TSA on glucocorticoid receptor (GR)-dependent transcription and we have related these effects to changes in the chromatin structure of a reporter mouse mammary tumor virus (MMTV) promoter. We show that TSA induces a low level of constitutive transcription. This correlates with a change of acetylation pattern and a more open chromatin structure over the MMTV chromatin, and with specific acetylation and remodeling events in the promoter region. Specifically, a repositioning of initially randomly positioned nucleosomes along the distal MMTV long terminal repeat is seen. This nucleosome rearrangement is similar to the translational nucleosome positioning that occurs upon hormone activation. We also note a reduced hormone response in the presence of TSA. TSA effects have for a long time been associated with transcriptional activation and chromatin opening through inhibition of the deacetylation of histones. However, our results and those of others show that TSA-induced changes in expression and chromatin structure can be quite different in different promoter contexts and, thus, the effects of TSA are more complex than previously believed.
Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, Stockholm, Sweden.
Carolina
C
Astrand
Tomas
T
Klenka
Orjan
O
Wrange
Sergey
S
Belikov
D000107:Acetylation; D000818:Animals; D002843:Chromatin / Q000187:drug effects* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D004126:Dimethylformamide / Q000494:pharmacology; D005938:Glucocorticoids / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D008836:Micrococcal Nuclease / Q000235:genetics / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020079:Terminal Repeat Sequences / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D014982:Xenopus laevis
D002843:Chromatin; D005938:Glucocorticoids; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D009707:Nucleosomes; D011965:Receptors, Glucocorticoid; C012589:trichostatin A; D004126:Dimethylformamide; D004247:DNA; D008836:Micrococcal Nuclease