Epigenetic Repression of RARRES1 Is Mediated by Methylation of a Proximal Promoter and a Loss of CTCF Binding
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{"title"=>"Epigenetic Repression of RARRES1 is mediated by methylation of a proximal promoter and a loss of CTCF binding", "type"=>"journal", "authors"=>[{"first_name"=>"Zhengang", "last_name"=>"Peng", "scopus_author_id"=>"54796980900"}, {"first_name"=>"Rulong", "last_name"=>"Shen", "scopus_author_id"=>"16403313600"}, {"first_name"=>"Ying Wei", "last_name"=>"Li", "scopus_author_id"=>"55919560300"}, {"first_name"=>"Kun Yu", "last_name"=>"Teng", "scopus_author_id"=>"55222001900"}, {"first_name"=>"Charles L.", "last_name"=>"Shapiro", "scopus_author_id"=>"7102469628"}, {"first_name"=>"Huey Jen L", "last_name"=>"Lin", "scopus_author_id"=>"18836418200"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pmid"=>"22615834", "pui"=>"364837495", "scopus"=>"2-s2.0-84861218306", "doi"=>"10.1371/journal.pone.0036891", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "sgr"=>"84861218306"}, "id"=>"e6de0e35-d659-37c3-b00f-416daddb7a2a", "abstract"=>"BACKGROUND: The cis-acting promoter element responsible for epigenetic silencing of retinoic acid receptor responder 1 (RARRES1) by methylation is unclear. Likewise, how aberrant methylation interplays effectors and thus affects breast neoplastic features remains largely unknown.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: We first compared methylation occurring at the sequences (-664~+420) flanking the RARRES1 promoter in primary breast carcinomas to that in adjacent benign tissues. Surprisingly, tumor cores displayed significantly elevated methylation occurring solely at the upstream region (-664~-86), while the downstream element (-85~+420) proximal to the transcriptional start site (+1) remained largely unchanged. Yet, hypermethylation at the former did not result in appreciable silencing effect. In contrast, the proximal sequence displayed full promoter activity and methylation of which remarkably silenced RARRES1 transcription. This phenomenon was recapitulated in breast cancer cell lines, in which methylation at the proximal region strikingly coincided with downregulation. We also discovered that CTCF occupancy was enriched at the unmethylayed promoter bound with transcription-active histone markings. Furthermore, knocking-down CTCF expression hampered RARRES1 expression, suggesting CTCF positively regulated RARRES1 transcription presumably by binding to unmethylated promoter poised at transcription-ready state. Moreover, RARRES1 restoration not only impeded cell invasion but also promoted death induced by chemotherapeutic agents, denoting its tumor suppressive effect. Its role of attenuating invasion agreed with data generated from clinical specimens revealing that RARRES1 was generally downregulated in metastatic lymph nodes compared to the tumor cores.\\n\\nCONCLUSION/SIGNIFICANCE: This report delineated silencing of RARRES1 by hypermethylation is occurring at a proximal promoter element and is associated with a loss of binding to CTCF, an activator for RARRES1 expression. We also revealed the tumor suppressive roles exerted by RARRES1 in part by promoting breast epithelial cell death and by impeding cell invasion that is an important property for metastatic spread.", "link"=>"http://www.mendeley.com/research/epigenetic-repression-rarres1-mediated-methylation-proximal-promoter-loss-ctcf-binding", "reader_count"=>36, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Student > Doctoral Student"=>1, "Researcher"=>6, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>4, "Student > Bachelor"=>3, "Professor"=>2, "Unspecified"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Student > Doctoral Student"=>1, "Researcher"=>6, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>4, "Student > Bachelor"=>3, "Professor"=>2, "Unspecified"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>6, "Agricultural and Biological Sciences"=>22, "Medicine and Dentistry"=>5, "Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>22}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>1, "Mexico"=>1, "Germany"=>1, "India"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/637335"], "description"=>"<p>(A) Degrees of methylation occurring at the sequence flanking the <i>RARRES1</i> promoter (D+P) in normal breast epithelia and in cancer cell lines were ranked in an ascending order. Names of breast cancer cell lines were color-coded as: blue for luminal (<i>N</i> = 3), red for basal (<i>N</i> = 3) and green for mesenchymal (<i>N</i> = 3). (B) Relative RARRES1 expression in the indicated cells was evaluated by RT-qPCR and compared to that of MCF10A set as 1. ND, too low to be detected. (C) Scatter plot depicted an inverse correlation between RARRES1 expression and methylation occurring at either overall (−664∼+420, upper panel) or merely at the proximal region (−85∼+420, lower panel) in the aforementioned cell lines. (D) Treatment of SUM149 and SK-BR-3 cells with epigenetic drugs reversed the silencing effect and re-stored expression inferred by increased transcripts assessed by RT-PCR.</p>", "links"=>[], "tags"=>["proximal", "promoter", "rendered", "cancer"], "article_id"=>307821, "categories"=>["Cancer", "Cell Biology", "Genetics"], "users"=>["Zhengang Peng", "Rulong Shen", "Ying-Wei Li", "Kun-Yu Teng", "Charles L. Shapiro", "Huey-Jen L. Lin"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036891.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Methylation_at_the_region_proximal_to_the_RARRES1_promoter_rendered_silencing_effect_in_breast_cancer_cell_lines_/307821", "title"=>"Methylation at the region proximal to the <i>RARRES1</i> promoter rendered silencing effect in breast cancer cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-17 02:10:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/637462"], "description"=>"<p>(A) A schematic map revealed <i>RARRES1</i> promoter as well as its flanking sequences (denoted as R1∼R6) that were interrogated by ChIP-qPCR assay. (B) RARRES1-expressing MCF10A and -silenced SUM159 cells were subjected to ChIP-qPCR analysis for assessing the abundance of histone modifications. (C) CTCF occupancy was enriched in regions R4 in MCF10A but was absent in SUM159. Quality reliance is assured by a negligible binding to normal IgG.</p>", "links"=>[], "tags"=>["promoter", "was", "poised", "histone", "marking", "co-occupied", "ctcf", "expressing", "cells", "occupancy", "repressive", "h3k27me3", "depleted", "binding", "non-expressing"], "article_id"=>307931, "categories"=>["Cancer", "Cell Biology", "Genetics"], "users"=>["Zhengang Peng", "Rulong Shen", "Ying-Wei Li", "Kun-Yu Teng", "Charles L. Shapiro", "Huey-Jen L. Lin"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036891.g004", "stats"=>{"downloads"=>1, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RARRES1_promoter_was_poised_by_active_histone_marking_H3K4me2_and_co_occupied_with_CTCF_in_the_expressing_cells_MCF10A_as_opposed_to_the_occupancy_of_repressive_histone_H3K27me3_with_depleted_CTCF_binding_in_the_non_expressing_cells_SUM159_/307931", "title"=>"<i>RARRES1</i> promoter was poised by active histone marking (H3K4me2) and co-occupied with CTCF in the expressing cells (MCF10A), as opposed to the occupancy of repressive histone H3K27me3 with depleted CTCF binding in the non-expressing cells (SUM159).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-17 02:12:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/637587"], "description"=>"<p>(A) MCF10A cells were transduced with recombinant viruses to express either control or CTCF shRNA, followed by a Western blot analysis to capture the expression of CTCF (upper) or GAPDH (lower, served as a loading control). (B) Same cells were subjected to ChIP-qPCR analysis for assessing CTCF occupancy at regions R1-R6. (C) Knocking down CTCF resulted in silencing of RARRES1 that can be inferred by RT-qPCR analysis. Significant loss of transcript was denoted by * if p<0.01.</p>", "links"=>[], "tags"=>["ctcf", "resulted", "rarres1"], "article_id"=>308076, "categories"=>["Cancer", "Cell Biology", "Genetics"], "users"=>["Zhengang Peng", "Rulong Shen", "Ying-Wei Li", "Kun-Yu Teng", "Charles L. Shapiro", "Huey-Jen L. Lin"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036891.g005", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Knocking_down_CTCF_resulted_in_a_significant_loss_of_RARRES1_expression_/308076", "title"=>"Knocking down CTCF resulted in a significant loss of RARRES1 expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-17 02:14:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/637097"], "description"=>"<p>(A) Primary breast tumors along with their matched adjacent benign tissues (total 18 cases examined) were analyzed for DNA methylation by MassARRAY assay. Within the schema flanking <i>RARRES1</i> promoter, each vertical line represented a single CpG site, while each circle at the lower panel indicated various methylation level of a CpG unit that contained either single or multiple CpG sites. Sample names were outlined at the left, while the average methylation levels occurring at the underlined region (−664∼−86) were denoted at the right. T, tumor core; N, adjacent benign. (B) Dot plot revealed a significant gain of methylation at the underlined region in tumor cores compared to the ones in adjacent benign tissues (p<0.001). (C) Scatter plot inferred expression of RARRES1 was unrelated to level of methylation at the same underlined sequences. (D) Similar levels of RARRES1 expression between the breast tumor cores and the adjacent benign tissues were demonstrated by immunohistochemical staining. A representative image was captured from case 1 (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036891#pone.0036891.s005\" target=\"_blank\">Table S2</a>).</p>", "links"=>[], "tags"=>["occurring", "sequences", "upstream", "distal", "promoter", "exerted", "negligible"], "article_id"=>307578, "categories"=>["Cancer", "Cell Biology", "Genetics"], "users"=>["Zhengang Peng", "Rulong Shen", "Ying-Wei Li", "Kun-Yu Teng", "Charles L. Shapiro", "Huey-Jen L. Lin"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036891.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Methylation_occurring_at_sequences_upstream_and_distal_to_the_RARRES1_promoter_exerted_a_negligible_silencing_effect_in_primary_breast_tumors_/307578", "title"=>"Methylation occurring at sequences upstream and distal to the <i>RARRES1</i> promoter exerted a negligible silencing effect in primary breast tumors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-17 02:06:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/637657"], "description"=>"<p>(A) Re-expression of RARRES1 was induced in SUM159 variants after been incubated with Doxycycline (Dox) for various durations. Expression level was assessed by RT-qPCR (upper) and by Western blot analysis (lower), in comparison with an internal control GAPDH. (B) The same RARRES1-expressing SUM159 variant was either untreated or treated with Dox for 24 hours. The resultant cells were then challenged with various doses of Paclitaxel and Doxorubicin for two days and the survival cells were quantified by MTT assays. * inferred a significant change of cell viability (p<0.05). (C) Upper, a significant loss of invasive ability occurred in SUM159 variant re-expressing RARRES1. *, p<0.05. Lower, representative IHC images indicated a reduced RARRES1 expression in metastatic lymph nodes compared to primary breast tumors of the same patient (cases 2 shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036891#pone.0036891.s005\" target=\"_blank\">Tables S2</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036891#pone.0036891.s007\" target=\"_blank\">S4</a>).</p>", "links"=>[], "tags"=>["restoration", "impeded", "promoted"], "article_id"=>308145, "categories"=>["Cancer", "Cell Biology", "Genetics"], "users"=>["Zhengang Peng", "Rulong Shen", "Ying-Wei Li", "Kun-Yu Teng", "Charles L. Shapiro", "Huey-Jen L. Lin"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036891.g006", "stats"=>{"downloads"=>1, "page_views"=>33, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RARRES1_restoration_impeded_invasion_and_promoted_cell_death_/308145", "title"=>"RARRES1 restoration impeded invasion and promoted cell death.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-17 02:15:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/328795", "https://ndownloader.figshare.com/files/328883", "https://ndownloader.figshare.com/files/328911", "https://ndownloader.figshare.com/files/328967", "https://ndownloader.figshare.com/files/329055", "https://ndownloader.figshare.com/files/329139", "https://ndownloader.figshare.com/files/329241"], "description"=>"<div><h3>Background</h3><p>The <em>cis</em>-acting promoter element responsible for epigenetic silencing of <em>retinoic acid receptor responder 1</em> (<em>RARRES1</em>) by methylation is unclear. Likewise, how aberrant methylation interplays effectors and thus affects breast neoplastic features remains largely unknown.</p> <h3>Methodology/Principal Findings</h3><p>We first compared methylation occurring at the sequences (−664∼+420) flanking the <em>RARRES1</em> promoter in primary breast carcinomas to that in adjacent benign tissues. Surprisingly, tumor cores displayed significantly elevated methylation occurring solely at the upstream region (−664∼−86), while the downstream element (−85∼+420) proximal to the transcriptional start site (+1) remained largely unchanged. Yet, hypermethylation at the former did not result in appreciable silencing effect. In contrast, the proximal sequence displayed full promoter activity and methylation of which remarkably silenced <em>RARRES1</em> transcription. This phenomenon was recapitulated in breast cancer cell lines, in which methylation at the proximal region strikingly coincided with downregulation. We also discovered that CTCF occupancy was enriched at the unmethylayed promoter bound with transcription-active histone markings. Furthermore, knocking-down <em>CTCF</em> expression hampered RARRES1 expression, suggesting CTCF positively regulated <em>RARRES1</em> transcription presumably by binding to unmethylated promoter poised at transcription-ready state. Moreover, RARRES1 restoration not only impeded cell invasion but also promoted death induced by chemotherapeutic agents, denoting its tumor suppressive effect. Its role of attenuating invasion agreed with data generated from clinical specimens revealing that <em>RARRES1</em> was generally downregulated in metastatic lymph nodes compared to the tumor cores.</p> <h3>Conclusion/Significance</h3><p>This report delineated silencing of <em>RARRES1</em> by hypermethylation is occurring at a proximal promoter element and is associated with a loss of binding to CTCF, an activator for RARRES1 expression. We also revealed the tumor suppressive roles exerted by RARRES1 in part by promoting breast epithelial cell death and by impeding cell invasion that is an important property for metastatic spread.</p> </div>", "links"=>[], "tags"=>["epigenetic", "repression", "mediated", "methylation", "proximal", "promoter", "ctcf", "binding"], "article_id"=>124924, "categories"=>["Cancer", "Cell Biology", "Genetics"], "users"=>["Zhengang Peng", "Rulong Shen", "Ying-Wei Li", "Kun-Yu Teng", "Charles L. Shapiro", "Huey-Jen L. Lin"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0036891.s001", "https://dx.doi.org/10.1371/journal.pone.0036891.s002", "https://dx.doi.org/10.1371/journal.pone.0036891.s003", "https://dx.doi.org/10.1371/journal.pone.0036891.s004", "https://dx.doi.org/10.1371/journal.pone.0036891.s005", "https://dx.doi.org/10.1371/journal.pone.0036891.s006", "https://dx.doi.org/10.1371/journal.pone.0036891.s007"], "stats"=>{"downloads"=>21, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Epigenetic_Repression_of_RARRES1_Is_Mediated_by_Methylation_of_a_Proximal_Promoter_and_a_Loss_of_CTCF_Binding/124924", "title"=>"Epigenetic Repression of <em>RARRES1</em> Is Mediated by Methylation of a Proximal Promoter and a Loss of CTCF Binding", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-05-17 01:22:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/637242"], "description"=>"<p>(A) Fragments (D, P and D+P) flanking the <i>RARRES1</i> promoter were inserted to pGL3-Basic luciferase vector. (B) The resultant constructs were transfected into 293T cells followed by luciferase assays for assessing promoter activity. While activity from pGL3-Basic was set as 1, the one from Renilla luciferase vector served as an internal control for normalization. (C) D, P, or D+P regions were either mockly treated (Unmethylated, U) or methylated <i>in vitro</i> (M). The resultant fragments were further ligated to the luciferase vector backbone (pGL3-Basic) and subject to luciferase analysis. Significance of difference (if p<0.01) was denoted by comparing unmethylated P and D+P to that of D (marked by *) or methylated (M) to those of unmethylated counterparts (U) in samples P and D+P (denoted as #). (D) Various promoter activities were associated with swap constructs (D and P), respectively derived from either the unmethylated (U) or methylated (M) state. The full activity was obtained from unmethylated D(U)+P(U) set as 1, while * depicted a significant loss ascribed to methylation (p<0.01).</p>", "links"=>[], "tags"=>["sequences", "proximal", "promoter", "displayed", "suppressed", "dna"], "article_id"=>307724, "categories"=>["Cancer", "Cell Biology", "Genetics"], "users"=>["Zhengang Peng", "Rulong Shen", "Ying-Wei Li", "Kun-Yu Teng", "Charles L. Shapiro", "Huey-Jen L. Lin"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036891.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Flanking_sequences_proximal_to_the_RARRES1_promoter_displayed_a_full_promoter_activity_that_can_be_suppressed_by_DNA_methylation_/307724", "title"=>"Flanking sequences proximal to the <i>RARRES1</i> promoter displayed a full promoter activity that can be suppressed by DNA methylation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-17 02:08:44"}

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Relative Metric

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