DETERMINANTS OF CHROMATIN DISRUPTION AND TRANSCRIPTIONAL REGULATION INSTIGATED BY THE THYROID-HORMONE RECEPTOR - HORMONE-REGULATED CHROMATIN DISRUPTION IS NOT SUFFICIENT FOR TRANSCRIPTIONAL ACTIVATION

Chromatin disruption and transcriptional activation are both thyroid h ormone-dependent processes regulated by the heterodimer of thyroid hor mone receptor and 9-cis retinoic acid receptor (TR-RXR). In the absenc e of hormone, TR-RXR binds to nucleosomal DNA, locally disrupts histon e-DNA contacts and generates a DNase I-hypersensitive site, Chromatin- bound unliganded TR-RXR silences transcription of the Xenopus TR beta A gene within a canonical nucleosomal array. On addition of hormone, t he receptor directs the extensive further disruption of chromatin stru cture over several hundred base pairs of DNA and activates transcripti on. We define a domain of the TR protein necessary for directing this extensive hormone-dependent chromatin disruption Particular TR-RXR het erodimers containing mutations in this domain are able to bind both ho rmone and their thyroid hormone receptor recognition element (TRE) wit hin chromatin, yet are unable to direct the extensive hormone-dependen t disruption of chromatin or to activate transcription, We distinguish the hormone-dependent disruption of chromatin and transcriptional act ivation as independently regulated events through the mutagenesis of b asal promoter elements and by altering the position and number of TREs within the TR beta A promoter, Chromatin disruption alone on a minich romosome is shown to be insufficient for transcriptional activation of the TR beta A gene.