Alteration of Large-Scale Chromatin Structure by Estrogen Receptor

Nye, Anne C.; Rajendran, Ramji R.; Stenoien, David L.; Mancini, Michael A.; Katzenellenbogen, Benita S.; Belmont, Andrew S.

doi:10.1128/mcb.22.10.3437-3449.2002

Cited by 95 publications

(89 citation statements)

References 57 publications

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“…More recently, footprinting and ChIP studies have revealed the association (Kim et al 2000, Shang et al 2000 and cyclic recruitment (Reid et al 2003) of ERα to estrogen-responsive promoters in the absence of ligand. These findings parallel those of Belmont's group who, reconstructing and visualizing transcriptional regulation and chromatin structure, has found that the apo-ERα was able to decondense chromatin (Nye et al 2002). In this experimental system, decondensation of large-scale chromatin was independent of helix 12 and did not require transcriptional activation by ERα, ligand-induced coactivator binding, or histone hyperacetylation.…”

Section: Role In Repressing Apo-erαsupporting

confidence: 88%

Estrogen receptor corepressors -- a role in human breast cancer?

Dobrzycka

Townson

Jiang³

et al. 2003

Endocrine-Related Cancer

118

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Estrogen receptor α (ERα) has an established role in promoting breast cancer. Transcriptional activation by ERα is a complex and multistep process, and it is influenced by coactivator and corepressor proteins that can either positively or negatively modulate ERα-mediated transcriptional activity. Corepressors are proposed to provide a counterbalance to the estrogen-induced transactivation, and represent a potential mechanism employed by the cell to regulate hormonal responses. In this review, we present evidence from tissue culture, animal and clinical studies, supporting the hypothesis that corepressors are crucial regulators of ERα-mediated action, and that their loss could promote breast cancer development and resistance to endocrine therapy. We propose that ERα corepressors play an important biological role by controlling the magnitude of the estrogen response, mediating antiestrogen inhibition of ERα, repressing DNA-bound ERα in the absence of the ligand, and conferring active repression of ERα-downregulated genes. Different ERα corepressors regulate steroid receptor activity through a variety of mechanisms, including formation of multiprotein complexes that are able to affect chromatin remodeling, histone deacetylation, or basal transcription. Other mechanisms include competition with coactivators, interference with DNA binding and ERα homodimerization, alteration of ERα stability, sequestration of ERα in the cytoplasm, and effects on RNA processing. Most ERα corepressors can control the receptor's activity through more than one mechanism, and it is possible that the synergy between different pathways cooperates to fully inhibit ERα transcriptional activity, and create an integrated response to a variety of different cellular signaling pathways. We will discuss the role of corepressors in tumor suppression and the link they might present between ERα regulation and DNA repair. Finally, we will discuss major challenges in the field and speculate on the exciting findings that await us in the next few years.

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Section: Role In Repressing Apo-erαsupporting

confidence: 88%

Estrogen receptor corepressors -- a role in human breast cancer?

Dobrzycka

Townson

Jiang³

et al. 2003

Endocrine-Related Cancer

118

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“…NYE5 (a GFP-lac rep expression plasmid) was made in a manner similar to NYE4 (8) except that an AscI site was added at the end of GFP-lac rep by silent mutations A3167G and A3170C just downstream of a PvuII site. NYE4 and NYE5 are functionally equivalent in coding for the dimer, tight binding form of the lac repressor.…”

Section: Subcloningmentioning

confidence: 99%

“…We previously used this system to investigate the effects of ER on large-scale chromatin structure (8). In that work, we investigated the structure of the fibers produced by targeting various mutations and truncations of the ER to the A03_1 lac operator array.…”

Section: Experimental Designmentioning

confidence: 99%

“…The GFP-lac rep-DEF of ER fusion protein contains the D, E, and F domains of the ER, including the ligand-inducible activation function 2 (AF-2). We previously determined that this region of ER unfolds chromatin dramatically only in the absence of the hormone estradiol (8). The data are presented in two ways: as box plots (Fig.…”

Section: Validation Of the Automated Datamentioning

confidence: 99%

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Automated microscopy identifies estrogen receptor subdomains with large‐scale chromatin structure unfolding activity

2004

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Background:Recently, several transcription factors were found to possess large-scale chromatin unfolding activity; these include the VP16 acidic activation domain, BRCA1, E2F1, p53, and the glucocorticoid and estrogen steroid receptors. In these studies, proteins were fluorescently labeled and targeted to a multimerized array of DNA sequences in mammalian cultured cells, and changes in the appearance and/or size of the array were observed. This type of experiment is impeded by the low throughput of traditional microscopy. Methods: We report the application of automated microscopy to provide unattended, rapid, quantitative measurements of fluorescently labeled chromosome regions. Results: The automated image collection routine produced results comparable to results previously obtained by manual methods and was significantly faster. Using this

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“…Throughout most of the cell cycle, this amplified chromosome region is condensed into a compact mass. Targeting certain transcriptional activators to this heterochromatic locus via a lac repressor fusion protein leads to large-scale decondensation of this region (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

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confidence: 99%

Upstream binding factor association induces large-scale chromatin decondensation

Chen

Belmont

Huang

2004

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

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The function of upstream binding factor (UBF), an essential component of the RNA polymerase (pol) I preinitiation complex, is unclear. Recently, UBF was found distributed throughout ribosomal gene repeats rather than being restricted to promoter regions. This observation has led to the speculation that one role of UBF binding may be to induce chromatin remodeling. To directly evaluate the impact of UBF on chromatin structure, we used an in vivo assay in which UBF is targeted via a lac repressor fusion protein to a heterochromatic, amplified chromosome region containing lac operator repeats. We show that the association of UBF with this locus induces large-scale chromatin decondensation. This process does not appear to involve common remodeling complexes, including SWI͞SNF and histone acetyltransferases, and is independent of histone H3 lysine 9 acetylation. However, UBF recruits the pol I-specific, TATA box-binding protein containing complex SL1 and pol I subunits. Our results suggest a working hypothesis in which the dynamic association of UBF with ribosomal DNA clusters recruits the pol I transcription machinery and maintains these loci in a transcriptionally competent configuration. These studies also provide an in vivo model simulating ribosomal DNA transactivation outside the nucleolus, allowing temporal and spatial analyses of chromatin remodeling and assembly of the pol I transcription machinery. R ibosomal RNA (rRNA) is encoded by tandem arrays of rDNA genes that are organized in human cells into nucleolar organizing regions (NORs) located on five chromosome pairs. A specific set of transcription factors is dedicated to transcription of rDNA into pre-rRNA that is subsequently processed into 28S, 18S, and 5.8S rRNAs. The rRNAs are packaged with ribosomal proteins to form the large and small subunits of ribosomes (1). Transcription of rDNA is highly specific and extensively regulated, involving a large number of proteins (1-3). Studies based mostly on in vitro assays suggest that transcriptional activation of rDNA involves association of the preinitiation complex with the promoter region followed by recruitment of other factors and RNA polymerase (pol) I subunits. The preinitiation complex has been shown to contain upstream binding factor (UBF) (4) and the TATA box-binding protein (TBP) containing complex SL1 (5).UBF is highly conserved in vertebrate cells from Xenopus to human. It contains five high mobility group boxes, an N terminus necessary for nuclear translocation, and a highly acidic C terminus essential for nucleolar localization (4, 6, 7). Although UBF is involved in pol I transcriptional activation, the mechanism by which it acts remains unclear. The consensus derived mostly from in vitro and some in vivo correlative studies places UBF at the early steps of rDNA transactivation (1, 2, 8). Analyses using in vitro transcription assays indicate that UBF initially binds DNA and is necessary for SL1 binding to form the preinitiation complex (9). Recently, UBF was discovered to literally coat DNA thro...

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Alteration of Large-Scale Chromatin Structure by Estrogen Receptor

Cited by 95 publications

References 57 publications

Estrogen receptor corepressors -- a role in human breast cancer?

Estrogen receptor corepressors -- a role in human breast cancer?

Automated microscopy identifies estrogen receptor subdomains with large‐scale chromatin structure unfolding activity

Upstream binding factor association induces large-scale chromatin decondensation

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