Cohesin Is Required for Activation of MYC by Estradiol
Publication Date
November 08, 2012
Journal
PLOS ONE
Authors
Miranda V. Mc Ewan, Michael R. Eccles & Julia A. Horsfield
Volume
7
Issue
11
Pages
e49160
DOI
https://dx.plos.org/10.1371/journal.pone.0049160
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0049160
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/23145106
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493498
Europe PMC
http://europepmc.org/abstract/MED/23145106
Web of Science
000312269500080
Scopus
84869053071
Mendeley
http://www.mendeley.com/research/cohesin-required-activation-myc-estradiol
Events
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Mendeley | Further Information

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Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/545923"], "description"=>"<p>MCF7 cells were transfected with Control or RAD21 siRNA for 48 hours and treated with estradiol for 45 minutes before fixation. ERα binding was analyzed by ChIP. Data shown is fold enrichment; binding was calculated relative to input chromatin and normalized against the negative control site (NEG) where no binding is observed. The bar graph shows the mean +/− SEM of three independent experiments. The marks *** and **** indicate a highly significant (p<0.005 and p<0.001 respectively) decrease in ERα-binding in RAD21 siRNA transfected cells relative to Control siRNA transfected cells. A schematic of primer locations is shown below the histogram. ChIP primer sequences are listed in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s004\" target=\"_blank\">Table S1</a>. A scale diagram of primer positions relative to the <i>MYC</i> gene and promoters is shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s003\" target=\"_blank\">Figure S3</a>. <b>B)</b><b>Total ERα levels are not affected by RAD21 depletion.</b> ERα levels remained unchanged 48 hours after transfection with 10 nM RAD21 siRNA. <b>C)</b><b>RAD21 depletion does not affect ERE-mediated transcription of luciferase in a plasmid-based reporter system</b>. MCF7 cells were transfected for 48 hours with Control, RAD21 or ESR1 siRNA and either a negative control (NEG) plasmid, a positive control plasmid (POS) or a plasmid encoding the firefly luciferase reporter gene under the control of 5 EREs. Cells were treated with vehicle (V) or estradiol (E) for 24 hours before luciferase activity was measured. Firefly luciferase activity was normalized to <i>Renilla</i> luciferase activity, and expressed as relative luciferase units (RLU). The mean ± SEM (n  = 5 biological replicates) is shown. There was no significant difference in estradiol activation of ERE-luciferase between Control and RAD21-depleted cells.</p>", "links"=>[], "tags"=>["binding", "locus", "exogenous", "rad21", "abrogates", "upstream"], "article_id"=>216416, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology", "Genetics"], "users"=>["Miranda V. McEwan", "Michael R. Eccles", "Julia A. Horsfield"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049160.g006", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RAD21_is_necessary_for_ER_binding_within_the_MYC_locus_but_not_an_exogenous_ERE_A_RAD21_silencing_abrogates_ER_binding_upstream_of_MYC_/216416", "title"=>"RAD21 is necessary for ERα binding within the <i>MYC</i> locus but not an exogenous ERE. A) RAD21 silencing abrogates ERα binding upstream of <i>MYC</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-08 01:46:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/546064"], "description"=>"<p>ERα levels were depleted 48 hours after ESR1 siRNA transfection (10 nM). <b>B) ERα depletion prevents enrichment of RAD21 binding in response to estradiol.</b> MCF7 cells were transfected with Control or ESR1 siRNA for 48 hours and treated with estradiol (E) or vehicle (V) for 45 minutes before being fixed. RAD21 binding was analyzed using ChIP. Data shown is fold enrichment; binding was calculated relative input chromatin and normalized against the negative control site (NEG) where no binding was observed. The bar graph shows the mean +/− SEM of three independent experiments. The symbols *, ** and *** indicate significant (p<0.05, p<0.01 and p<0.005, respectively) enrichment in RAD21 binding in Control siRNA transfected cells treated with estradiol. There was no significant difference in RAD21 binding between ESR1 siRNA transfected cells treated with vehicle or with estradiol. ChIP primer sequences are listed in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s004\" target=\"_blank\">Table S1</a>. A scale diagram of primer positions relative to the <i>MYC</i> gene and promoters is shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s003\" target=\"_blank\">Figure S3</a>.</p>", "links"=>[], "tags"=>["estradiol-mediated", "induction", "rad21", "binding", "locus", "mcf7", "cancer"], "article_id"=>216553, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology", "Genetics"], "users"=>["Miranda V. McEwan", "Michael R. Eccles", "Julia A. Horsfield"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049160.g008", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ER_is_necessary_for_estradiol_mediated_induction_of_RAD21_binding_within_the_MYC_locus_in_MCF7_breast_cancer_cells_A_ESR1_silencing_in_MCF7_cells_/216553", "title"=>"ERα is necessary for estradiol-mediated induction of RAD21 binding within the <i>MYC</i> locus in MCF7 breast cancer cells. A) <i>ESR1</i> silencing in MCF7 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-08 01:49:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/545768"], "description"=>"<p>MCF7 cells were fixed following treatment with vehicle (V) or estradiol (E) for 45 minutes. RAD21 binding was analyzed by ChIP. Data are presented as fold enrichment relative to input chromatin and normalized against a negative site (NEG) where no binding was observed. The bar graph represents the mean +/− SEM of three independent experiments. The symbol * indicates a significant increase (p<0.05) in RAD21 binding between vehicle and estradiol treated cells. A schematic of primer locations is shown below the histogram. ChIP primer sequences are listed in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s004\" target=\"_blank\">Table S1</a>. A scale diagram of primer positions relative to the <i>MYC</i> gene and promoters is shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s003\" target=\"_blank\">Figure S3</a>.</p>", "links"=>[], "tags"=>["binding", "enriched", "estradiol", "sites", "8q24"], "article_id"=>216263, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology", "Genetics"], "users"=>["Miranda V. McEwan", "Michael R. Eccles", "Julia A. Horsfield"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049160.g004", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RAD21_binding_is_enriched_by_estradiol_treatment_at_MYC_regulatory_sites_within_the_8q24_region_/216263", "title"=>"RAD21 binding is enriched by estradiol treatment at <i>MYC</i> regulatory sites within the 8q24 region.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-08 01:44:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/545556"], "description"=>"<p><b>A)</b><b><i>RAD21</i></b><b> silencing in MCF7 cells.</b> RAD21 protein levels were reduced 24 hours after transfection and completely depleted 48 hours after transfection with 10 nM RAD21 siRNA <b>B)</b><b>RAD21 positively regulates </b><b><i>MYC</i></b><b> in MCF7</b><b>cells</b>. Relative levels of <i>MYC</i> mRNA in Control (CON) and RAD21 siRNA transfected MCF7 cells were determined by qRT-PCR. Columns show the average values of relative normalized expression from three independent experiments. The * symbol indicates a significant (p<0.05) reduction in <i>MYC</i> transcript levels in RAD21 depleted MCF7 cells compared with cells transfected with Control siRNA. <b>C)</b><b>Estradiol-activation of </b><b><i>MYC</i></b><b> is ERα- and RAD21-dependent</b>. MCF7 cells were transfected with Control (CON), RAD21 or ESR1 siRNA for 48 hours and then treated with vehicle (V) or estradiol (E) for 6 hours. <i>MYC</i> transcript levels are shown relative to Control siRNA + V treated cells. The results shown are the mean (+/− SEM) of 3 biological replicates. The **** symbol indicates a highly significant (p<0.001) reduction in <i>MYC</i> expression in RAD21 and ESR1 siRNA transfected cells treated with estradiol compared with Control siRNA transfected cells treated with estradiol.</p>", "links"=>[], "tags"=>["rad21", "prevents", "estradiol", "activation", "mcf7"], "article_id"=>216048, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology", "Genetics"], "users"=>["Miranda V. McEwan", "Michael R. Eccles", "Julia A. Horsfield"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049160.g001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Depletion_of_RAD21_prevents_estradiol_activation_of_MYC_in_MCF7_cells_/216048", "title"=>"Depletion of RAD21 prevents estradiol activation of <i>MYC</i> in MCF7 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-08 01:40:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/545855"], "description"=>"<p>RAD21 binding in MCF7, T47D and MDA-MB-231 cell lines was analyzed by ChIP. RAD21 binding is shown as fold enrichment relative to input chromatin and normalized against a negative site (NEG) where no binding was observed. The bar graph represents the mean +/− SEM of three independent experiments. The symbols * and ** indicate significant differences (p<0.05 and p<0.01 respectively) in RAD21 binding relative to the MCF7 cell line. A schematic of primer locations is shown below the histogram. ChIP primer sequences are listed in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s004\" target=\"_blank\">Table S1</a>. A scale diagram of primer positions relative to the <i>MYC</i> gene and promoters is shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s003\" target=\"_blank\">Figure S3</a>.</p>", "links"=>[], "tags"=>["binding", "elements", "varies", "cancer"], "article_id"=>216349, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology", "Genetics"], "users"=>["Miranda V. McEwan", "Michael R. Eccles", "Julia A. Horsfield"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049160.g005", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RAD21_binding_to_MYC_regulatory_elements_varies_between_breast_cancer_cell_lines_/216349", "title"=>"RAD21 binding to <i>MYC</i> regulatory elements varies between breast cancer cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-08 01:45:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/545705"], "description"=>"<p>Genomic binding of cohesin and ERα were identified by ChIP-seq (Schmidt <i>et al</i>, 2010). Peaks of cohesin- (blue), estradiol-induced cohesin- (Cohesin + E, purple) and ERα-binding are indicated above the genome annotation of <i>MYC. </i><b>B)</b><b>Schematic of position of ChIP primers.</b> Specific regions of interest are magnified to indicate genomic binding identified by ChIP-seq and the location of primers used for Chromatin Immunoprecipitation (ChIP). Primer sequences are listed in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s004\" target=\"_blank\">Table S1</a>. A scale diagram of primer positions relative to the <i>MYC</i> gene and promoters is shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s003\" target=\"_blank\">Figure S3</a>.</p>", "links"=>[], "tags"=>["cohesin", "binding", "overlap", "schematic", "locations", "cohesin-", "er-binding", "8q24"], "article_id"=>216189, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology", "Genetics"], "users"=>["Miranda V. McEwan", "Michael R. Eccles", "Julia A. Horsfield"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049160.g003", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ER_and_cohesin_binding_overlap_at_several_MYC_regulatory_sites_A_Schematic_of_locations_of_cohesin_and_ER_binding_within_the_8q24_region_/216189", "title"=>"ER and cohesin binding overlap at several <i>MYC</i> regulatory sites. A) Schematic of locations of cohesin- and ER-binding within the 8q24 region.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-08 01:43:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/546123"], "description"=>"<p>T47D cells were transfected with Control or ESR1 siRNA for 48 hours and treated with estradiol (E) or vehicle (V) for 45 minutes before being fixed. RAD21 binding was analyzed using ChIP. Data shown is fold enrichment; binding was calculated relative input chromatin and normalized against the negative control site (NEG) where no binding was observed. The bar graph shows the mean +/− SEM of three independent experiments. The symbols ** and **** indicate significant (p<0.01 and p<0.0001, respectively) enrichment in RAD21 binding in Control siRNA transfected cells treated with estradiol. There was no significant difference in RAD21 binding between ESR1 siRNA transfected cells treated with vehicle or with estradiol. ChIP primer sequences are listed in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s004\" target=\"_blank\">Table S1</a>. A scale diagram of primer positions relative to the <i>MYC</i> gene and promoters is shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s003\" target=\"_blank\">Figure S3</a>.</p>", "links"=>[], "tags"=>["depletion", "prevents", "enrichment", "rad21", "binding"], "article_id"=>216619, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology", "Genetics"], "users"=>["Miranda V. McEwan", "Michael R. Eccles", "Julia A. Horsfield"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049160.g009", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ER_945_depletion_prevents_enrichment_of_RAD21_binding_in_response_to_estradiol_/216619", "title"=>"ERα depletion prevents enrichment of RAD21 binding in response to estradiol.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-08 01:50:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/546006"], "description"=>"<p>T47D cells were transfected with Control or RAD21 siRNA for 48 hours and treated with estradiol for 45 minutes before fixation. ERα binding was analyzed by ChIP. Data shown is fold enrichment; binding was calculated relative to input chromatin and normalized against the negative control site (NEG) where no binding is observed. The bar graph shows the mean +/− SEM of three independent experiments. The marks **, *** and **** indicate a highly significant (p<0.01, p<0.005 and p<0.001 respectively) decrease in ERα-binding in RAD21 siRNA transfected cells relative to Control siRNA transfected cells. A schematic of primer locations is shown below the histogram. ChIP primer sequences are listed in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s004\" target=\"_blank\">Table S1</a>. A scale diagram of primer positions relative to the <i>MYC</i> gene and promoters is shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049160#pone.0049160.s003\" target=\"_blank\">Figure S3</a>.</p>", "links"=>[], "tags"=>["depletion", "binding", "upstream"], "article_id"=>216503, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology", "Genetics"], "users"=>["Miranda V. McEwan", "Michael R. Eccles", "Julia A. Horsfield"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049160.g007", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RAD21_depletion_reduces_ER_binding_upstream_of_MYC_/216503", "title"=>"RAD21 depletion reduces ERα binding upstream of <i>MYC</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-08 01:48:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/545626"], "description"=>"<p><b>A)</b><b><i>RAD21</i></b><b> silencing in T47D cells.</b> RAD21 protein levels were reduced 48 hours after transfection with 10 nM RAD21 siRNA as described in B. <b>B)</b><b>Estradiol-activation of </b><b><i>MYC</i></b><b> is RAD21-dependent in T47D cells</b>. T47D cells were transfected with Control (CON) or RAD21 (RAD) siRNA for 48 hours and then treated with vehicle (V) or estradiol (E) for 6 hours. <i>MYC</i> transcript levels are shown relative to Control siRNA + V treated cells. The ** symbols indicate a significant (p<0.01) reduction in <i>MYC</i> expression in RAD21-depleted cells relative to Control siRNA transfected cells, and between estradiol treated Control cells and estradiol treated RAD21-depleted T47D cells. <b>C)</b><b>RAD21 silencing in MDA-MB-231 cells.</b> RAD21 protein levels were reduced 48 hours after siRNA transfection with 10 nM RAD21 siRNA. <b>D) RAD21 positively regulates </b><b><i>MYC</i></b><b> in ER-negative MDA-MB-231 cells.</b> Relative levels of <i>MYC</i> mRNA in Control (CON) and RAD21 siRNA transfected MDA-MB-231 cells were determined by qRT-PCR. All results are representative or the mean +/− SEM of three independent experiments. The symbol ** indicates a significant (p<0.01) difference in <i>MYC</i> transcript levels between Control siRNA and RAD21 siRNA transfected cells MDA-MB-231 cells.</p>", "links"=>[], "tags"=>["rad21", "positively", "regulates", "er-positive", "er-negative", "cancer"], "article_id"=>216114, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology", "Genetics"], "users"=>["Miranda V. McEwan", "Michael R. Eccles", "Julia A. Horsfield"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0049160.g002", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Depletion_of_RAD21_positively_regulates_MYC_expression_in_both_ER_positive_and_ER_negative_breast_cancer_cells_/216114", "title"=>"Depletion of RAD21 positively regulates <i>MYC</i> expression in both ER-positive and ER-negative breast cancer cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-11-08 01:41:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/292937", "https://ndownloader.figshare.com/files/292994", "https://ndownloader.figshare.com/files/293063", "https://ndownloader.figshare.com/files/293116"], "description"=>"<div><p>Cohesin is best known as a multi-subunit protein complex that holds together replicated sister chromatids from S phase until G2. Cohesin also has an important role in the regulation of gene expression. We previously demonstrated that the cohesin complex positively regulates expression of the oncogene <em>MYC</em>. Cell proliferation driven by MYC contributes to many cancers, including breast cancer. The <em>MYC</em> oncogene is estrogen-responsive and a transcriptional target of estrogen receptor alpha (ERα). Estrogen-induced cohesin binding sites coincide with ERα binding at the <em>MYC</em> locus, raising the possibility that cohesin and ERα combine actions to regulate <em>MYC</em> transcription. The objective of this study was to investigate a putative role for cohesin in estrogen induction of <em>MYC</em> expression. We found that siRNA-targeted depletion of a cohesin subunit, RAD21, decreased <em>MYC</em> expression in ER-positive (MCF7 and T47D) and ER-negative (MDA-MB-231) breast cancer cell lines. In addition, RAD21 depletion blocked estradiol-mediated activation of <em>MYC</em> in ER-positive cell lines, and decreased ERα binding to estrogen response elements (EREs) upstream of <em>MYC</em>, without affecting total ERα levels. Treatment of MCF7 cells with estradiol caused enrichment of RAD21 binding at upstream enhancers and at the P2 promoter of <em>MYC</em>. Enriched binding at all sites, except the P2 promoter, was dependent on ERα. Since RAD21 depletion did not affect transcription driven by an exogenous reporter construct containing a naked ERE, chromatin-based mechanisms are likely to be involved in cohesin-dependent <em>MYC</em> transcription. This study demonstrates that ERα activation of <em>MYC</em> can be modulated by cohesin. Together, these results demonstrate a novel role for cohesin in estrogen-mediated regulation of <em>MYC</em> and the first evidence that cohesin plays a role in ERα binding.</p> </div>", "links"=>[], "tags"=>["cohesin", "activation", "estradiol"], "article_id"=>117663, "categories"=>["Molecular Biology", "Biochemistry", "Cancer", "Cell Biology", "Genetics"], "users"=>["Miranda V. McEwan", "Michael R. Eccles", "Julia A. Horsfield"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0049160.s001", "https://dx.doi.org/10.1371/journal.pone.0049160.s002", "https://dx.doi.org/10.1371/journal.pone.0049160.s003", "https://dx.doi.org/10.1371/journal.pone.0049160.s004"], "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Cohesin_Is_Required_for_Activation_of_MYC_by_Estradiol__/117663", "title"=>"Cohesin Is Required for Activation of <em>MYC</em> by Estradiol", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-11-08 02:07:43"}

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Relative Metric

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