Chromatin Structure and Gene Regulation by Steroid Hormones

Hormonal induction of the Mouse Mammary Tumor Virus (MMTV) is mediated by a complex hormone responsive region (HRR) composed of 5 hormone receptor binding sites, upstream of a binding site for the transcription factor NFI, two octamer motifs, and the TATA box. Optimal induction requires the integrity of all these cis-acting elements, but the corresponding factors can not bind to free DNA simultaneously. In cells carrying chromosomal MMTV sequences, the HRR is organized into a phased nucleosome which allows binding of the hormone receptors to two of their five cognate sites, while precluding access to the NFI site and to the octamer motifs. Receptor binding is determined by the rotational orientation of the relevant major grooves, but the NFI site is inaccessible, no matter the helical orientation, as long as it is included within a positioned nucleosome. Hormone treatment leads to a rapid alteration in chromatin structure that makes the dyad axis of the regulatory nucleosome more accessible to digestion by DNaseI and restriction enzymes. Concomitantly, all five receptors binding sites, the NFI, and the octamer motifs are occupied, while the nucleosome remains in place, suggesting that it may facilitate full loading of the promoter with transcription factors. This notion is supported by studies on the influence of nucleosome depletion on basal and induced expression of MMTV promoter in yeast. The MMTV promoter exhibits a positioned nucleosome inS. cerevisiaewith similar location as in metazoan cells. Hormonal induction of MMTV transcription in yeast depends on a functional synergism between the glucocorticoid receptor (GR) and NFI.