The Glucocorticoid Receptor: Rapid Exchange with Regulatory Sites in Living Cells

McNally, James G.; Müller, Waltraud G.; Walker, Dawn A.; Wolford, Ronald G.; Hager, Gordon L.

doi:10.1126/science.287.5456.1262

Cited by 731 publications

(645 citation statements)

References 31 publications

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“…In 3134 cells, 200 copies of the MMTV-LTR with 800-1200 GRbinding sites are stably integrated in a head-to-tail orientation into the centromeric region of chromosome 4 (McNally et al, 2000). The 3617 cell line expressing GFP-GR under control of a tetracycline-repressible (Tet-Off) system is generated by stable transfection of 3134 cells (Walker et al, 1999).…”

Section: Cell Culture and Stable Cell Linesmentioning

confidence: 99%

“…In 3134 (murine mammary adenocarcinoma) cells, 200 copies of the MMTV-LTR with 800 -1200 GR-binding sites are stably integrated in a head-to-tail orientation near the centromere of chromosome 4. Previous studies have indicated that the hormone response of the MMTV-LTR array as a unit is indistinguishable from that of a single integrated copy of the viral LTR (Fragoso et al, 1998;Kramer et al, 1999;McNally et al, 2000). The array, therefore, provides a good model system to examine the in vivo recruitment of chromatin-remodeling complexes to their target promoter.…”

Section: Brg1 and Brm Chromatin-remodeling Complexes Are Selectively mentioning

confidence: 99%

“…To further understand the process by which chromatin-remodeling complexes are recruited and regulate target genes to modulate transcription, we have directly visualized the sequence of gene expression events involving the SWI/SNF complex in mouse mammary adenocarcinoma cells that contain a tandem repeat of stably integrated copies of the MMTV-LTR (mouse mammary tumor virus-long terminal repeat). This array which contains 800-1200 binding sites for GR can be visualized by using green fluorescent protein (GFP)-tagged versions of steroid receptors and associated cofactors (Kramer et al, 1999;McNally et al, 2000;Rayasam et al, 2005). We have investigated the molecular basis by which SWI/SNF regulates transcription as well as its influence on the chromatin structure of a steroid hormone-responsive promoter array.…”

Section: Introductionmentioning

confidence: 99%

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Chromatin Remodeling Complexes Interact Dynamically with a Glucocorticoid Receptor–regulated Promoter

Johnson

Elbi

Parekh

et al. 2008

MBoC

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Brahma (BRM) and Brahma-related gene 1 (BRG1) are the ATP-dependent catalytic subunits of the SWI/SNF family of chromatin-remodeling complexes. These complexes are involved in essential processes such as cell cycle, growth, differentiation, and cancer. Using imaging approaches in a cell line that harbors tandem repeats of stably integrated copies of the steroid responsive MMTV-LTR (mouse mammary tumor virus-long terminal repeat), we show that BRG1 and BRM are recruited to the MMTV promoter in a hormone-dependent manner. The recruitment of BRG1 and BRM resulted in chromatin remodeling and decondensation of the MMTV repeat as demonstrated by an increase in the restriction enzyme accessibility and in the size of DNA fluorescence in situ hybridization (FISH) signals. This chromatin remodeling event was concomitant with an increased occupancy of RNA polymerase II and transcriptional activation at the MMTV promoter. The expression of ATPase-deficient forms of BRG1 (BRG1-K-R) or BRM (BRM-K-R) inhibited the remodeling of local and higher order MMTV chromatin structure and resulted in the attenuation of transcription. In vivo photobleaching experiments provided direct evidence that BRG1, BRG1-K-R, and BRM chromatin-remodeling complexes have distinct kinetic properties on the MMTV array, and they dynamically associate with and dissociate from MMTV chromatin in a manner dependent on hormone and a functional ATPase domain. Our data provide a kinetic and mechanistic basis for the BRG1 and BRM chromatin-remodeling complexes in regulating gene expression at a steroid hormone inducible promoter. INTRODUCTIONThe eukaryotic genome is organized into higher order chromatin structures in the nucleus. The regulation of eukaryotic gene expression in the context of chromatin is a complex event and is essential for numerous cellular processes (Lemon and Tjian, 2000;Orphanides and Reinberg, 2002;Labrador and Corces, 2002;Maniatis and Reed, 2002;Felsenfeld and Groudine, 2003;Roberts and Orkin, 2004). Maintenance, establishment, and modification of global chromatin organization and local chromatin structure are modulated by a large number of chromatin-binding proteins that generate transcriptionally permissive or repressed chromatin domains in response to environmental stimuli (Workman and Kingston, 1998;Peterson and Workman, 2000;Jones and Kadonaga, 2000;Wu and Grunstein, 2000;Wolffe and Hansen, 2001;Becker et al., 2002). The association of linker histones and nonhistone and heterochromatin-specific proteins such as high mobility group proteins and HP1 play key roles in the generation of higher order chromatin structures (Arents et al., 1991; Luger et al., 1997;Bustin, 1999;Eissenberg and Elgin, 2000;Hill, 2001;Thomas and Travers, 2001;Woodcock and Dimitrov, 2001;Grewal and Elgin, 2002;Bianchi and Agresti, 2005;Bustin et al., 2005;Verschure et al., 2005). The stearically restricted environment presented by chromatin is in part overcome by multisubunit protein complexes that enzymatically regulate chromatin structure. These complexes can e...

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Section: Cell Culture and Stable Cell Linesmentioning

confidence: 99%

Section: Brg1 and Brm Chromatin-remodeling Complexes Are Selectively mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chromatin Remodeling Complexes Interact Dynamically with a Glucocorticoid Receptor–regulated Promoter

Johnson

Elbi

Parekh

et al. 2008

MBoC

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“…The punctate subnuclear localization and nuclear matrix association of acute lymphoblastic leukemia-1 (ALL-1) (55), the glucocorticoid receptor (56), the estrogen receptor (57), the androgen receptor (35), and the thyroid hormone receptor (58) are consistent with compartmentalization and focal concentrations of regulatory machinery for biologically responsive integration of regulatory signals. A clinically relevant example of perturbations in regulatory activity that result from modifications in the intranuclear distribution of receptors is illustrated by PML bodies (59).…”

Section: Nuclear Microenvironments: An Architecturalmentioning

confidence: 92%

“…BRCA1 and proliferating cell nuclear antigen) (26,67). Yet another biologically relevant example of combinatorial control is the focal assembly of regulatory machinery for glucocorticoid and estrogen-responsive gene expression (31,32,56,57). Similarly, the combinatorial organization of regulatory complexes that are responsible for chromatin structure, nucleosome organization, and dynamics of chromatin remodeling illustrates the scaffolding for factors that establish competency for transcriptional activation and/or suppression (Fig.…”

Section: Scaffolding Proteins Functionally Configure and Organizementioning

confidence: 99%

Intranuclear Trafficking: Organization and Assembly of Regulatory Machinery for Combinatorial Biological Control

Zaidi

Young

Choi

et al. 2004

Journal of Biological Chemistry

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The molecular logistics of nuclear regulatory processes necessitate temporal and spatial regulation of protein-protein and protein-DNA interactions in response to physiological cues. Biochemical, in situ, and in vivo genetic evidence demonstrates the requirement for intranuclear localization of regulatory complexes that functionally couple cellular responses to signals that mediate combinatorial control of gene expression. We have summarized evidence that subnuclear targeting of transcription factors mechanistically links gene expression with architectural organization and assembly of nuclear regulatory machinery for biological control. The compromised intranuclear targeting of regulatory proteins under pathological conditions provides options for the diagnosis and treatment of disease. An Architectural Perspective of CombinatorialGene Regulation Components of nuclear architecture are functionally linked to the organization and sorting of regulatory information in a manner that permits selective utilization (1-10). The primary level of nuclear organization, the representation and ordering of genes and promoter elements, provides alternatives for biological control. The molecular organization of regulatory elements, the overlap of regulatory sequences within promoter domains, and the multipartite composition of regulatory complexes increase options for responsiveness. From context dependence of modularly organized promoter sequences and juxtaposition of regulatory domains, parameters of the protein-DNA and protein-protein interactions that dictate the combinatorial assembly and organization of multicomponent regulatory complexes are emerging. Chromatin structure and nucleosome organization reduce distances between regulatory sequences, facilitate cross-talk between promoter elements, and render elements competent for interactions with positive and negative regulatory factors (11). Evidence is emerging for a "histone code" that (through the post-translational modifications of the highly conserved N-terminal tails of histones) defines the activity of a gene promoter. In addition, CpG methylation of specific promoters selectively silences the expression of tissue-specific genes in a manner that supports competency for progenitor cell differentiation with both options and constraints (12,13).The components of higher order nuclear architecture, which include nuclear pores, the nuclear matrix, and intranuclear domains, contribute to the bidirectional nucleocytoplasmic exchange of regulatory information as well as to the subnuclear distribution and activities of gene regulatory factors (1,10,14). Nuclear localization sequences and export signals within the proteins are recognized by transport machinery that mediates translocation of these proteins between cytoplasm and the nucleus (15). An additional level of regulation is provided by post-translational modifications of nuclear proteins. For example, TEL, a putative tumor suppressor, is exported out of the nucleus when sumoylated, which in turn impairs its ability to re...

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Features of nuclear architecture that influence gene expression in higher eukaryotes: Confronting the enigma of epigenetics

Jackson

2000

J. Cell. Biochem.

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Complex mechanisms that in¯uence gene expression in mammalian cells have been studied intensively over recent years. Genetic elements that control both the tissue speci®c patterns and levels of gene expression together with the proteins they bind have been characterised in detail and are clearly pivotal in activating pathways of gene expression. But it is also clear that the behaviour of these genetic elements is complicated by epigenetic factors, so that their introduction into cells with the necessary developmental historyÐand hence appropriate global concentrations of essential transcription factorsÐwill not guarantee the desired levels of transcription. Recent experiments have reinforced this view and con®rmed that apparently critical functions performed by de®ned genetic elements at certain chromosomal sites are not inevitably recapitulated at other chromosomal locations. Hence, a re-evaluation of the function of critical control elements is required using experimental systems that simplify the range of factors arising from local chromatin organisation. In this way, it should be possible to reveal the intricacies of gene expression that might eventually allow us to reproduce natural levels of expression from arti®cial gene constructs in human cells.

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The Glucocorticoid Receptor: Rapid Exchange with Regulatory Sites in Living Cells

Cited by 731 publications

References 31 publications

Chromatin Remodeling Complexes Interact Dynamically with a Glucocorticoid Receptor–regulated Promoter

Chromatin Remodeling Complexes Interact Dynamically with a Glucocorticoid Receptor–regulated Promoter

Intranuclear Trafficking: Organization and Assembly of Regulatory Machinery for Combinatorial Biological Control

Features of nuclear architecture that influence gene expression in higher eukaryotes: Confronting the enigma of epigenetics

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