Interaction of the Glucocorticoid Receptor with the Chromatin Landscape

John, Sam; Sabo, Peter J.; Johnson, Thomas A.; Sung, Myong-Hee; Biddie, Simon C.; Lightman, Stafford L.; Voss, Ty C.; Davis, Sean; Meltzer, Paul S.; Stamatoyannopoulos, J; Hager, Gordon L.

doi:10.1016/j.molcel.2008.02.010

Cited by 285 publications

(321 citation statements)

References 45 publications

(52 reference statements)

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“…3). This is in agreement with a recent genome-scale mapping of DNase I hypersensitive sites (DHS), which found that several loci exhibit tissue-specific DHS profile (37). Note that this mechanism of passive nucleosome eviction does not rely on recruitment of chromatin modification machinery, which may play a role in further destabilizing nucleosomes and expanding nucleosomefree regions.…”

Section: Resultssupporting

confidence: 90%

Nucleosome-mediated cooperativity between transcription factors

Mirny

2010

Proc. Natl. Acad. Sci. U.S.A.

300

166

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Cooperative binding of transcription factors (TFs) to promoters and other regulatory regions is essential for precise gene expression. The classical model of cooperativity requires direct interactions between TFs, thus constraining the arrangement of TF sites in regulatory regions. Recent genomic and functional studies, however, demonstrate a great deal of flexibility in such arrangements with variable distances, numbers of sites, and identities of TF sites located in cis-regulatory regions. Such flexibility is inconsistent with cooperativity by direct interactions between TFs. Here, we demonstrate that strong cooperativity among noninteracting TFs can be achieved by their competition with nucleosomes. We find that the mechanism of nucleosome-mediated cooperativity is analogous to cooperativity in another multimolecular complex: hemoglobin. This surprising analogy provides deep insights, with parallels between the heterotropic regulation of hemoglobin (e.g., the Bohr effect) and the roles of nucleosome-positioning sequences and chromatin modifications in gene expression. Nucleosome-mediated cooperativity is consistent with several experimental studies, is equally applicable to repressors and activators, allows substantial flexibility in and modularity of regulatory regions, and provides a rationale for a broad range of genomic and evolutionary observations. Striking parallels between cooperativity in hemoglobin and in transcriptional regulation point to a general mechanism that can be used in various biological systems.protein-DNA interactions | promoter | enhancer | histone | Monod-Wyman-Changeux

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Section: Resultssupporting

confidence: 90%

Nucleosome-mediated cooperativity between transcription factors

Mirny

2010

Proc. Natl. Acad. Sci. U.S.A.

300

166

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“…Enrichment of a remodeler with H2A.Z might provide one mechanism for increasing remodeling as has been indicated previously (7,15). Additionally, inclusion of H2A.Z in chromatin could effect the proficiency of the remodeling reaction itself.…”

Section: Resultsmentioning

confidence: 76%

“…On Drosophila melanogaster salivary gland chromosomes, H2A.Z colocalizes with the ISWI remodeling complex RSF (14). In humans, H2A.Z is detected at sites of transcriptionally regulated DNase I hypersensitivity; accessibility of DNase I to some of these sites is mediated by the Swi/Snf motor protein BRG1 (7). Furthermore, recruitment of BRG1 to ER␣-induced promoter TTF1 is dependent on H2A.Z deposition (15).…”

mentioning

confidence: 99%

Chromatin Remodeling by Imitation Switch (ISWI) Class ATP-dependent Remodelers Is Stimulated by Histone Variant H2A.Z

Goldman¹,

Garlick²,

Kingston³

2010

Journal of Biological Chemistry

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ATP-dependent chromatin remodeling complexes rearrange nucleosomes by altering the position of DNA around the histone octamer. Although chromatin remodelers and the histone variant H2A.Z colocalize on transcriptional control regions, whether H2A.Z directly affects remodeler association or activity is unclear. We determined the relative association of remodelers with H2A.Z chromatin and tested whether replacement of H2A.Z in a nucleosome altered the activity of remodeling enzymes. Many families of remodelers showed increased association with H2A.Z chromatin, but only the ISWI family of chromatin remodelers showed stimulated activity in vitro. An acidic patch on the nucleosome surface, extended by inclusion of H2A.Z in nucleosomes and essential for viability, is required for ISWI stimulation. We conclude that H2A.Z incorporation increases nucleosome remodeling activity of the largest class of mammalian remodelers (ISWI) and that it correlates with increased association of other remodelers to chromatin. This reveals two possible modes for regulation of a remodeler by a histone variant.

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“…Ligand binding drives GR transformation, involving N-terminal phosphorylation on S203 and S211 and rapid translocation to the nucleus requiring attachment to dynein by heat shock protein 90, immunophilins, and dynamitin (6). Once in the nucleus, GR binds directly to DNA to regulate transcription, or tethers to other DNA-bound transcription factors, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP1), to regulate their function (7)(8)(9)(10).…”

mentioning

confidence: 99%

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

Matthews

Berry

Morgan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily, which controls programs regulating cell proliferation, differentiation, and apoptosis. We have identified an unexpected role for GR in mitosis. We discovered that specifically modified GR species accumulate at the mitotic spindle during mitosis in a distribution that overlaps with Aurora kinases. We found that Aurora A was required to mediate mitosis-driven GR phosphorylation, but not recruitment of GR to the spindle. GR was necessary for mitotic progression, with increased time to complete mitosis, frequency of mitotic aberrations, and death in mitosis observed following GR knockdown. Complementation studies revealed an essential role for the GR ligand-binding domain, but no clear requirement for ligand binding in regulating chromosome segregation. The GR N-terminal domain, and specifically phosphosites S203 and S211, were not required. Reduced GR expression results in a cell cycle phenotype, with isolated cells from mouse and human subjects showing changes in chromosome content over prolonged passage. Furthermore, GR haploinsufficient mice have an increased incidence of tumor formation, and, strikingly, these tumors are further depleted for GR, implying additional GR loss as a consequence of cell transformation. We identified reduced GR expression in a panel of human liver, lung, prostate, colon, and breast cancers. We therefore reveal an unexpected role for the GR in promoting accurate chromosome segregation during mitosis, which is causally linked to tumorigenesis, making GR an authentic tumor suppressor gene.glucocorticoid receptor | mitosis | aneuploidy | DNA damage | cancer G lucocorticoids (Gcs) act through the glucocorticoid receptor (GR), a member of the nuclear hormone receptor superfamily, and a ligand-activated transcription factor (1-4). The GR is ubiquitously expressed and regulates energy metabolism, immunity, and cell fate decisions. The quiescent GR resides in the cytoplasm in a complex with heat shock proteins and immunophilins, attached to the microtubule architecture of the cell in a heat shock protein 90-dependent manner (5). Ligand binding drives GR transformation, involving N-terminal phosphorylation on S203 and S211 and rapid translocation to the nucleus requiring attachment to dynein by heat shock protein 90, immunophilins, and dynamitin (6). Once in the nucleus, GR binds directly to DNA to regulate transcription, or tethers to other DNA-bound transcription factors, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP1), to regulate their function (7-10).In mitosis, GR is phosphorylated on both S203 and S211, but in a ligand-independent manner (11), and more comprehensive phosphoproteomic analyses identify the presence of multiple N-terminal GR phosphoforms in purified mitotic spindle fractions (12). Although altered GR function in mitosis has been shown (11, 13, 14), the kinases responsible and cellular consequences have not been defined. The role of G...

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Interaction of the Glucocorticoid Receptor with the Chromatin Landscape

Cited by 285 publications

References 45 publications

Nucleosome-mediated cooperativity between transcription factors

Nucleosome-mediated cooperativity between transcription factors

Chromatin Remodeling by Imitation Switch (ISWI) Class ATP-dependent Remodelers Is Stimulated by Histone Variant H2A.Z

Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy

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