PROLONGED GLUCOCORTICOID EXPOSURE DEPHOSPHOUYLATES HISTONE H1 AND INACTIVATES THE MMTV PROMOTER

Glucocorticoids rapidly induce transcription from the mouse mammary tu mour virus (MMTV) promoter via a glucocorticoid receptor (GR)-mediated chromatin disruption event, This remodelling of chromatin is transien t such that upon prolonged exposure to hormone the promoter becomes re fractory to glucocorticoids, We demonstrate that this refractory state requires the continual presence of hormone and can be reversed lay it s removal. Our experiments show that the promoter is inactivated via a mechanism whereby histone H1 is dephosphorylated in response to gluco corticoids. Removal of glucocorticoids results in the rephosphorylatio n of histone H1 and the reacquisition of transcriptional competence by the promoter. This response is specific for the MMTV promoter assembl ed as chromatin and is not observed for another inducible gene or tran siently transfected MMTV DNA. Finally, we demonstrate that H1 on the M MTV promoter is dephosphorylated when the promoter is unresponsive to glucocorticoids, These studies indicate that phosphorylated H1 is inti mately linked with the GR-mediated disruption of MMTV chromatin in viv o.