Prolonged glucocorticoid exposure dephosphorylates histone H1 and inactivates the MMTV promoter.
Glucocorticoids rapidly induce transcription from the mouse mammary tumour virus (MMTV) promoter via a glucocorticoid receptor (GR)-mediated chromatin disruption event. This remodelling of chromatin is transient such that upon prolonged exposure to hormone the promoter becomes refractory to glucocorticoids. We demonstrate that this refractory state requires the continual presence of hormone and can be reversed by its removal. Our experiments show that the promoter is inactivated via a mechanism whereby histone H1 is dephosphorylated in response to glucocorticoids. Removal of glucocorticoids results in the rephosphorylation of histone H1 and the reacquisition of transcriptional competence by the promoter. This response is specific for the MMTV promoter assembled as chromatin and is not observed for another inducible gene or transiently transfected MMTV DNA. Finally, we demonstrate that H1 on the MMTV promoter is dephosphorylated when the promoter is unresponsive to glucocorticoids. These studies indicate that phosphorylated H1 is intimately linked with the GR-mediated disruption of MMTV chromatin in vivo.
Lee
H L
HL
Department of Obstetrics and Gynaecology, The University of Western Ontario, London Regional Cancer Centre, 790 Commissioners Road East, London, Ontario, Canada N6A 4L6.
Archer
T K
TK
D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004279:DNA, Viral / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D011965:Receptors, Glucocorticoid / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D014158:Transcription, Genetic / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology
D002843:Chromatin; D004279:DNA, Viral; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D006657:Histones; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D008668:Metallothionein; D011493:Protein Kinase C; D019311:Staurosporine