Glucocorticoid Receptor-Glucocorticoid Response Element Binding Stimulates Nucleosome Disruption by the SWI/SNF Complex

The cell cycle regulator, retinoblastoma protein, is known to potentiate glucocorticoid receptor-activated transcription through the interaction of its pocket domain with the transcription coactivator, hBRM. We now show that glucocorticoid receptor-induced apoptosis is also dependent on both the retinoblastoma protein and hBRM. p107 and p130, which share extensive sequence homology with the pocket domain of the retinoblastoma protein but not its N-terminal region, also interact with hBRM but do not support either glucocorticoid receptordependent activity. This difference arises from the divergent N-terminal domain of the retinoblastoma protein, which, when fused to the pocket domains, confers upon p107 and p130 the ability to influence glucocorticoid receptor activities. This effect probably results from the promotion of glucocorticoid receptor-targeted chromatin remodeling by the hBRM-containing SWI/SNF complex because the N-terminal domain of the retinoblastoma protein enhances glucocorticoid receptor-hBRM interactions. These results highlight that, besides the interaction between hBRM and the pocket domain of RB, the N-terminal region of the retinoblastoma protein is also essential for glucocorticoid receptor-induced apoptosis and the potentiation of glucocorticoid receptor-mediated transcription and provide a basis for functional distinction between the retinoblastoma protein and its homologues.

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Retinoblastoma Protein Is Functionally Distinct from Its Homologues in Affecting Glucocorticoid Receptor-mediated Transcription and Apoptosis

Singh

Chan

Hong

2001

“…Once GR is bound, it will greatly enhance NF1 and Oct1 binding (Fig. 7), presumably by chromatin opening via recruitment of nucleosome remodeling complex(es) (44,45). Hence, our results imply a more interactive cooperation between the DNA binding factors and chromatin, leading to a stepwise development of more activity-prone chromatin states with an ultimate end point of a transcriptional response.…”

Section: The Mechanism Of Nucleosome Positioning Of the Mmtv Ltr: Intmentioning

confidence: 99%

Nuclear Factor 1 and Octamer Transcription Factor 1 Binding Preset the Chromatin Structure of the Mouse Mammary Tumor Virus Promoter for Hormone Induction

Беликов

Holmqvist

Åstrand

et al. 2004

When the mouse mammary tumor virus (MMTV) is integrated into the genome of a mammalian cell, its long terminal repeat (LTR) harbors six specifically positioned nucleosomes. Transcription from the MMTV promoter is regulated by the glucocorticoid hormone via the glucocorticoid receptor (GR). The mechanism of the apparently constitutive nucleosome arrangement has remained unclear. Previous in vitro reconstitution of nucleosome(s) on small segments of the MMTV LTR suggested that the DNA sequence was decisive for the nucleosome arrangement. However, microinjection of MMTV LTR DNA in Xenopus oocytes rendered randomly distributed nucleosomes. This indicated that oocytes lack factor(s) that induces nucleosome positioning at the MMTV LTR in other cells. Here we demonstrate that specific and concomitant binding of nuclear factor 1 (NF1) and octamer factor 1 (Oct1) to their cognate sites within the MMTV promoter induce a partial nucleosome positioning that is an intermediary state between the randomly organized inactive promoter and the hormone and GR-activated promoter containing distinctly positioned nucleosomes. Oct1 and NF1 reciprocally facilitate each other's binding to the MMTV LTR in vivo. The NF1 and Oct1 binding also facilitate hormone-dependent GR-DNA interaction and result in a faster and stronger hormone response. Since NF1 and Oct1 generate an intermediary state of nucleosome positioning and enhance the hormone-induced response, we refer to this as a preset chromatin structure. We propose that this state of NF1 and Oct1-induced chromatin presetting mimics the early step(s) of chromatin remodeling involved in tissue-specific gene expression.

“…The role of ATP-dependent mechanisms such as SWI/SNF, Mi2/NURD, and ISWI (5) in nuclear receptor-mediated regulation has also been demonstrated. Studies using the glucocorticoid receptor on the mouse mammary tumor virus promoter, which has been shown to have positioned nucleosomes (6), have demonstrated a requirement for SWI-SNF complexes and their ligand-induced targeting to the promoter to activate gene expression (7)(8)(9)(10)(11). More recently, it has been demonstrated that glucocorticoid receptor activation induces nucleosome translational positioning on the mouse mammary tumor virus promoter (12).…”

mentioning

confidence: 99%

Chromatin Remodeling by the Thyroid Hormone Receptor in Regulation of the Thyroid-stimulating Hormone α-Subunit Promoter

Collingwood¹,

Urnov²,

Chatterjee³

et al. 2001

The chromatin architecture of a promoter is an important determinant of its transcriptional response. For most target genes, the thyroid hormone receptor (TR) activates gene expression in response to thyroid hormone (T 3 ). In contrast, the thyroid-stimulating hormone ␣-subunit (TSH␣) gene promoter is down-regulated by TR in the presence of T 3 . Here we utilize the capacity for the Xenopus oocyte to chromatinize exogenous nuclearinjected DNA to analyze the chromatin architecture of the TSH␣ promoter and how this changes upon TR-mediated regulation. Interestingly, in the oocyte, the TSH␣ promoter was positively regulated by T 3 . In the inactive state, the promoter contained six loosely positioned nucleosomes. The addition of TR/retinoid X receptor together had no effect on the chromatin structure, but the inclusion of T 3 induced strong positioning of a dinucleosome in the TSH␣ proximal promoter that was bordered by regions that were hypersensitive to cleavage by methidiumpropyl EDTA. We identified a novel thyroid response element that coincided with the proximal hypersensitive region. Furthermore, we examined the consequences of mutations in TR that impaired coactivator recruitment. In a comparison with the Xenopus TR␤A promoter, we found that the effects of these mutations on transactivation and chromatin remodeling were significantly more severe on the TSH␣ promoter.The molecular mechanism of nuclear hormone receptor-mediated gene regulation and the importance of chromatin structure to this process have been intensively investigated over the past decade. Although the packaging of DNA into dense chromatin is a barrier to transcription factor access, multiple mechanisms exist to overcome this obstacle and thereby facilitate regulation of gene expression (1-3). Regulation of the acetylation state of core nucleosomal histone proteins influences their interaction with DNA and, subsequently, the nucleosomal packing density and transcription factor accessibility to chromatin. Transcriptional repression by DNA-bound thyroid hormone receptor (TR) 1 in the absence of hormone (T 3 ) involves the recruitment of histone deacetylase-containing complexes that facilitate the formation of repressive chromatin structure. The addition of T 3 causes the release of the deacetylase complexes and stimulates transcriptional activation by the recruitment of coactivators that include acetyltransferase components (1-3). The acetyltransferases and deacetylases are numerous, but occur in discrete subcomplexes that may exhibit cell type and promoter context dependence (4). The role of ATP-dependent mechanisms such as SWI/SNF, Mi2/NURD, and ISWI (5) in nuclear receptor-mediated regulation has also been demonstrated. Studies using the glucocorticoid receptor on the mouse mammary tumor virus promoter, which has been shown to have positioned nucleosomes (6), have demonstrated a requirement for SWI-SNF complexes and their ligand-induced targeting to the promoter to activate gene expression (7-11). More recently, it has been demonstrated tha...