Graded Nodal/Activin Signaling Titrates Conversion of Quantitative Phospho-Smad2 Levels into Qualitative Embryonic Stem Cell Fate Decisions
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{"title"=>"Graded Nodal/Activin signaling titrates conversion of quantitative phospho-Smad2 levels into qualitative embryonic stem cell fate decisions", "type"=>"journal", "authors"=>[{"first_name"=>"Kian Leong", "last_name"=>"Lee", "scopus_author_id"=>"22634890000"}, {"first_name"=>"Sandy Keat", "last_name"=>"Lim", "scopus_author_id"=>"47761198700"}, {"first_name"=>"Yuriy Lvovich", "last_name"=>"Orlov", "scopus_author_id"=>"7102256498"}, {"first_name"=>"Le Yau", "last_name"=>"Yit", "scopus_author_id"=>"42062448600"}, {"first_name"=>"Henry", "last_name"=>"Yang", "scopus_author_id"=>"23468238300"}, {"first_name"=>"Lay Teng", "last_name"=>"Ang", "scopus_author_id"=>"35191580600"}, {"first_name"=>"Lorenz", "last_name"=>"Poellinger", "scopus_author_id"=>"7006544462"}, {"first_name"=>"Bing", "last_name"=>"Lim", "scopus_author_id"=>"7201984111"}], "year"=>2011, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537390", "scopus"=>"2-s2.0-79959814756", "pui"=>"362058241", "doi"=>"10.1371/journal.pgen.1002130", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "sgr"=>"79959814756", "pmid"=>"21731500"}, "id"=>"bcc54d38-07d4-387d-a841-c612dbbb75a1", "abstract"=>"Nodal and Activin are morphogens of the TGFbeta superfamily of signaling molecules that direct differential cell fate decisions in a dose- and distance-dependent manner. During early embryonic development the Nodal/Activin pathway is responsible for the specification of mesoderm, endoderm, node, and mesendoderm. In contradiction to this drive towards cellular differentiation, the pathway also plays important roles in the maintenance of self-renewal and pluripotency in embryonic and epiblast stem cells. The molecular basis behind stem cell interpretation of Nodal/Activin signaling gradients and the undertaking of disparate cell fate decisions remains poorly understood. Here, we show that any perturbation of endogenous signaling levels in mouse embryonic stem cells leads to their exit from self-renewal towards divergent differentiation programs. Increasing Nodal signals above basal levels by direct stimulation with Activin promotes differentiation towards the mesendodermal lineages while repression of signaling with the specific Nodal/Activin receptor inhibitor SB431542 induces trophectodermal differentiation. To address how quantitative Nodal/Activin signals are translated qualitatively into distinct cell fates decisions, we performed chromatin immunoprecipitation of phospho-Smad2, the primary downstream transcriptional factor of the Nodal/Activin pathway, followed by massively parallel sequencing, and show that phospho-Smad2 binds to and regulates distinct subsets of target genes in a dose-dependent manner. Crucially, Nodal/Activin signaling directly controls the Oct4 master regulator of pluripotency by graded phospho-Smad2 binding in the promoter region. Hence stem cells interpret and carry out differential Nodal/Activin signaling instructions via a corresponding gradient of Smad2 phosphorylation that selectively titrates self-renewal against alternative differentiation programs by direct regulation of distinct target gene subsets and Oct4 expression.", "link"=>"http://www.mendeley.com/research/graded-nodalactivin-signaling-titrates-conversion-quantitative-phosphosmad2-levels-qualitative-embry", "reader_count"=>113, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>8, "Researcher"=>29, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>41, "Student > Postgraduate"=>4, "Other"=>2, "Student > Master"=>12, "Student > Bachelor"=>6, "Lecturer"=>2, "Professor"=>4}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>8, "Researcher"=>29, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>41, "Student > Postgraduate"=>4, "Other"=>2, "Student > Master"=>12, "Student > Bachelor"=>6, "Lecturer"=>2, "Professor"=>4}, "reader_count_by_subject_area"=>{"Engineering"=>2, "Biochemistry, Genetics and Molecular Biology"=>15, "Mathematics"=>1, "Agricultural and Biological Sciences"=>86, "Medicine and Dentistry"=>6, "Arts and Humanities"=>1, "Chemistry"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Chemistry"=>{"Chemistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>86}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>15}, "Mathematics"=>{"Mathematics"=>1}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"Republic of Singapore"=>1, "Canada"=>1, "Argentina"=>1, "Hong Kong"=>1, "United States"=>5, "Japan"=>1, "Brazil"=>1, "Portugal"=>1, "Germany"=>1}, "group_count"=>4}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/763234"], "description"=>"<p>(A) Proportional Venn diagram of overlapping and treatment specific pSmad2 binding peaks identified by ChIP-Seq from same passage ES cells cultured for 18 hours in Activin (ACT), DMSO control or SB in KSR media. Overlaps were defined using genomic coordinates of the start and end of peak positions identified with the MACS program using the same parameters for each treatment. Total numbers of peaks are stated for each condition and percentage of peaks in each Venn diagram segment is indicated in parentheses. (B) Graph showing frequency of pSmad2 peaks with respect to distribution in the indicated genomic locations including the transcriptional start sites (TSS) and transcriptional termination sites (TTS) relative to mouse RefSeq genes. Frequency is expressed as percentage of all pSmad2 binding peaks in conditions of high (Activin), medium (DMSO) and low (SB) signaling. (C) High resolution view of pSmad2 binding frequency within +/−2 kb of the TSS of target genes. Genomic distance is expressed in base pairs (bp) upstream (negative) and downstream (positive) of the TSS while frequency is shown as percentage of pSmad2 binding peaks binned in 50 bp intervals out of the total number of peaks for each treatment.</p>", "links"=>[], "tags"=>["binding", "es", "genome", "changes", "dynamically", "dose-dependent"], "article_id"=>433600, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Kian Leong Lee", "Sandy Keat Lim", "Yuriy Lvovich Orlov", "Le Yau Yit", "Henry Yang", "Lay Teng Ang", "Lorenz Poellinger", "Bing Lim"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002130.g004", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Phospho_Smad2_Binding_to_the_Global_ES_Cell_Genome_Changes_Dynamically_in_a_Dose_Dependent_Manner_/433600", "title"=>"Phospho-Smad2 Binding to the Global ES Cell Genome Changes Dynamically in a Dose-Dependent Manner.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-06-23 01:00:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/763348"], "description"=>"<p>(A) Plot of relationship between pSmad2 binding affinity and expression levels of associated target genes in the Activin, DMSO and SB conditions. Horizontal axis shows ∼8000 RefSeq microarray targets ranked based on normalized log<sub>2</sub> expression with a cutoff of 5.5 to exclude non-expressing genes and non-functional probes. The largest pSmad2 ChIP-Seq peaks occurring within +/-50 kb of the RefSeq genes were identified for each condition, normalized to average DMSO enrichments and subjected to a 500 gene moving average calculation on the vertical axis. (B) Plot showing frequency distribution of basic CAGA Smad-binding DNA element (SBE) sequence in 100 base pair (bp) intervals up- and downstream of ChIP-Seq peak positions. Horizontal axis shows distance in bp from the center (broken red line) of ChIP-Seq peaks and vertical axis shows frequency of CAGA motifs in each interval. The frequency of CAGA sequences in 10,000 random mouse genome locations was computed as a control for comparison (black line). (C) Plot of frequency distribution for the canonical Smad CAGAC sequence in intervals around ChIP-Seq peak positions using the same control calculations as in (B). Insert shows the logo of the Smad binding motif (TRANSFAC PWM SMAD_Q6_01) containing the CAGAC sequence. (D) Graph showing the sequence and frequency of the top 6-mer motifs in Activin, DMSO and SB. The motifs were defined by the Weeder program using sequences that occur only in the center of ChIP-Seq peaks. The frequency is expressed as fraction of +/–25 bp sequences spanning ChIP-Seq peaks containing the indicated motifs. CAGA containing 6-mers are highlighted in red. (E) 8-mer motifs defined by Weeder program in top 1000 ChIP-Seq peaks ranked by enrichments in +/−50 bp intervals for Activin, DMSO, SB and combined conditions correspondingly. Transcription factors binding to sequences similar to these motifs identified by the STAMP program using TRANSFAC PWM are indicated with corresponding p-values.</p>", "links"=>[], "tags"=>["increases", "phospho-smad2", "demonstrates", "dose-dependent", "affinity", "dna"], "article_id"=>433709, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Kian Leong Lee", "Sandy Keat Lim", "Yuriy Lvovich Orlov", "Le Yau Yit", "Henry Yang", "Lay Teng Ang", "Lorenz Poellinger", "Bing Lim"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002130.g005", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Target_Gene_Expression_Increases_with_Phospho_Smad2_Binding_Which_Demonstrates_Dose_Dependent_Affinity_for_Specific_DNA_Motifs_/433709", "title"=>"Target Gene Expression Increases with Phospho-Smad2 Binding, Which Demonstrates Dose-Dependent Affinity for Specific DNA Motifs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-06-23 01:01:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/762847"], "description"=>"<p>Real-time PCR quantification of changes in mRNA levels for (A) <i>Pitx2</i>, (B) <i>Lefty2</i> and (C) <i>Smad7</i> in mouse ES cells during a 0 to 24 hours time course under graded Nodal/Activin signaling conditions. High signaling was induced by direct treatment with 25 ng/ml Activin (red), low signaling with 10 uM of SB431542 inhibitor (green) and a control treatment with 1/5000 dilution of DMSO carrier (blue) was carried out following pretreatment of all cells for 6 hours in chemically defined KSR media with 10 µM SB (−6 to 0 hours). β-actin was used as a housekeeping control and error bars show s.e.m for n = 3 replicates.</p>", "links"=>[], "tags"=>["transcriptional", "targets", "graded"], "article_id"=>433214, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Kian Leong Lee", "Sandy Keat Lim", "Yuriy Lvovich Orlov", "Le Yau Yit", "Henry Yang", "Lay Teng Ang", "Lorenz Poellinger", "Bing Lim"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002130.g001", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pitx2_Lefty2_and_Smad7_Are_Transcriptional_Targets_of_Graded_Nodal_Activin_Signaling_/433214", "title"=>"<i>Pitx2</i>, <i>Lefty2</i>, and <i>Smad7</i> Are Transcriptional Targets of Graded Nodal/Activin Signaling.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-06-23 00:53:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/763677"], "description"=>"<p>UCSC Genome Browser plot of the <i>Oct4</i> genetic locus showing pSmad2 ChIP-Seq enrichment on the vertical scale in ES cells subjected to Activin (red), DMSO control (blue) and SB (green) treatments with genomic distance in bp on the horizontal scale. Colored bars show ChIP-Seq peak positions and normalized enrichments for each treatment. (B) 503 bp sequence of the <i>Oct4</i> promoter region marked with asterisk (*) in (A). Sequences in yellow show canonical CAGA SBEs or their inverted sequence TCTG while the strong CAGAC SBE is highlighted in blue. Sequences in red boxes denote where mutations were made in the indicated luciferase constructs. (C) Firefly luciferase assays of the 503 bp sequence cloned into the <i>pGL4.23</i> reporter construct (<i>pGL4.23 Oct4</i>) or mutated in the strong CAGAC SBE (<i>pGL4.23 m4 Oct4</i>) or mutated in CAGAC and the two flanking CAGA sites (<i>pGL4.23 m345 Oct4</i>). The constructs were transfected into ES cells treated with Activin (dark gray bars), DMSO control (light gray) and SB (white). Discontinuous vertical scale shows relative Firefly luciferase levels normalized to the co-transfection <i>pGL4.75</i> Renilla luciferase control. Error bars provide s.e.m. for n = 8 replicates. (D) Real-time PCR quantitation of endogenous <i>Oct4</i> expression in ES cells treated for 0 to 48 hours in SB (gray bars) compared to DMSO (white bars) after normalizing to the <i>Ywhaz</i> housekeeping control. Vertical axis shows fold change over the 0 h control in each treatment. Error bars show s.e.m. for n = 8 replicates. (E) Western blot of endogenous Oct4 protein levels in ES cells after treatment with SB or DMSO control in a 0 to 24 hour time course. Pcna was used as a loading control in both conditions. Densitometry plot shows Oct4 protein quantitation after normalizing to the respective Pcna loading control with the relative level at 0 hours for each treatment at 100%.</p>", "links"=>[], "tags"=>["signaling", "graded", "phospho-smad2", "recruitment"], "article_id"=>434043, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Kian Leong Lee", "Sandy Keat Lim", "Yuriy Lvovich Orlov", "Le Yau Yit", "Henry Yang", "Lay Teng Ang", "Lorenz Poellinger", "Bing Lim"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002130.g007", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Oct4_Is_a_Direct_Target_of_Nodal_Activin_Signaling_via_Graded_Phospho_Smad2_Recruitment_to_the_Promoter_/434043", "title"=>"<i>Oct4</i> Is a Direct Target of Nodal/Activin Signaling via Graded Phospho-Smad2 Recruitment to the Promoter.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-06-23 01:07:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/763086"], "description"=>"<p>(A) Heatmap showing microarray analysis of ES cells after 18 hours treatment with Activin (ACT), SB or DMSO vehicle control in KSR media. Transcript levels are expressed as log<sub>2</sub> fold change over the average of DMSO controls with red showing upregulation and green showing downregulation in n = 4 biological replicates from passage numbers 20 to 24 (P20-P24). Highlighted gene names indicate known roles or domains of expression in endoderm (red), mesoderm (blue), trophectoderm (green) or cancer (magenta). Color bar shows fold change in gene expression on a log<sub>2</sub> scale. (B) RT-PCR validation of target genes identified in the microarrays that are specifically regulated in ACT and/or SB treatments compared to the DMSO control. <i>Ywhaz</i> was used as a housekeeping control.</p>", "links"=>[], "tags"=>["signaling", "leads", "transcriptional", "subsets"], "article_id"=>433452, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Kian Leong Lee", "Sandy Keat Lim", "Yuriy Lvovich Orlov", "Le Yau Yit", "Henry Yang", "Lay Teng Ang", "Lorenz Poellinger", "Bing Lim"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002130.g003", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Increased_and_Decreased_Nodal_Activin_Signaling_Leads_to_Transcriptional_Regulation_of_Specific_Subsets_of_Target_Genes_/433452", "title"=>"Increased and Decreased Nodal/Activin Signaling Leads to Transcriptional Regulation of Specific Subsets of Target Genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-06-23 00:57:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/763833"], "description"=>"<p>Schema of the components and signal transduction of the Nodal/Activin pathway starting with different concentrations of ligands external to the ES cell lipid bilayer membrane and terminating with the pSmad2 transcriptional complex regulating <i>Oct4</i> and different subsets of target genes in the nucleus. Red arrows show the signal transduction circuit, black arrows show transcription and translation of pSmad2 target genes while green inhibitory lines indicate negative feedback. Protein names in red are targets identified in the microarray analysis and/or pSmad2 ChIP-Seq. Color gradients from red to green denote components exhibiting a dose-dependent response from high (+) to low (–) activity. Plots represent the graded, high and low signaling dominant models of pSmad2 binding during differential signaling with the vertical axis showing the level of binding against the horizontal axis with increasing signaling levels from left to right. Different cell fate decisions and the events triggering them are indicated by lines and arrows in red to green color gradients.</p>", "links"=>[], "tags"=>["es", "decisions", "directed", "graded"], "article_id"=>434197, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Kian Leong Lee", "Sandy Keat Lim", "Yuriy Lvovich Orlov", "Le Yau Yit", "Henry Yang", "Lay Teng Ang", "Lorenz Poellinger", "Bing Lim"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002130.g008", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_of_the_Mechanism_of_ES_Cell_Fate_Decisions_Directed_by_Graded_Nodal_Activin_Signaling_/434197", "title"=>"Model of the Mechanism of ES Cell Fate Decisions Directed by Graded Nodal/Activin Signaling.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-06-23 01:09:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/762965"], "description"=>"<p>(A) Western blot and densitometry quantitation of Smad2 phosphorylation in ES cells after 18 hours stimulation with Activin (ACT) and inhibition with SB-431542 (SB) compared to DMSO vehicle control at the indicated doses in chemically defined KSR media. The same blot was stripped and reprobed with total Smad2 and Pcna loading control antibodies. Secondary band in the total Smad2 blot corresponds to cross-reaction with total Smad3. Graph shows densitometry measurements of pSmad2 protein bands relative to total Smad2 in each treatment with the DMSO control at 100%. (B) Real-time PCR analysis of early cell fate markers in differentiated ES cells after 6 days treatment in ACT, DMSO and SB normalized to β-actin housekeeping control. Top panel shows induction of markers in ACT treatments expressed as fold change over the control KSR media. Bottom panel shows fold change in marker expression during SB treatment compared to KSR media supplemented with 1/5000 DMSO vehicle. Error bars show standard error of the mean (s.e.m) for n = 4 replicates.</p>", "links"=>[], "tags"=>["phosphorylation", "induction", "decisions", "differential"], "article_id"=>433332, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Kian Leong Lee", "Sandy Keat Lim", "Yuriy Lvovich Orlov", "Le Yau Yit", "Henry Yang", "Lay Teng Ang", "Lorenz Poellinger", "Bing Lim"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002130.g002", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Smad2_Phosphorylation_and_Induction_of_Distinct_Cell_Fate_Decisions_Are_Determined_by_Differential_Nodal_Activin_Signaling_/433332", "title"=>"Smad2 Phosphorylation and Induction of Distinct Cell Fate Decisions Are Determined by Differential Nodal/Activin Signaling.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-06-23 00:55:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/383343", "https://ndownloader.figshare.com/files/383462", "https://ndownloader.figshare.com/files/383612", "https://ndownloader.figshare.com/files/383677", "https://ndownloader.figshare.com/files/383759", "https://ndownloader.figshare.com/files/383835", "https://ndownloader.figshare.com/files/383897", "https://ndownloader.figshare.com/files/383976", "https://ndownloader.figshare.com/files/384021", "https://ndownloader.figshare.com/files/384078"], "description"=>"<div><p>Nodal and Activin are morphogens of the TGFbeta superfamily of signaling molecules that direct differential cell fate decisions in a dose- and distance-dependent manner. During early embryonic development the Nodal/Activin pathway is responsible for the specification of mesoderm, endoderm, node, and mesendoderm. In contradiction to this drive towards cellular differentiation, the pathway also plays important roles in the maintenance of self-renewal and pluripotency in embryonic and epiblast stem cells. The molecular basis behind stem cell interpretation of Nodal/Activin signaling gradients and the undertaking of disparate cell fate decisions remains poorly understood. Here, we show that any perturbation of endogenous signaling levels in mouse embryonic stem cells leads to their exit from self-renewal towards divergent differentiation programs. Increasing Nodal signals above basal levels by direct stimulation with Activin promotes differentiation towards the mesendodermal lineages while repression of signaling with the specific Nodal/Activin receptor inhibitor SB431542 induces trophectodermal differentiation. To address how quantitative Nodal/Activin signals are translated qualitatively into distinct cell fates decisions, we performed chromatin immunoprecipitation of phospho-Smad2, the primary downstream transcriptional factor of the Nodal/Activin pathway, followed by massively parallel sequencing, and show that phospho-Smad2 binds to and regulates distinct subsets of target genes in a dose-dependent manner. Crucially, Nodal/Activin signaling directly controls the <em>Oct4</em> master regulator of pluripotency by graded phospho-Smad2 binding in the promoter region. Hence stem cells interpret and carry out differential Nodal/Activin signaling instructions via a corresponding gradient of Smad2 phosphorylation that selectively titrates self-renewal against alternative differentiation programs by direct regulation of distinct target gene subsets and <em>Oct4</em> expression.</p> </div>", "links"=>[], "tags"=>["graded", "signaling", "titrates", "quantitative", "phospho-smad2", "levels", "qualitative", "embryonic", "decisions"], "article_id"=>135708, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Kian Leong Lee", "Sandy Keat Lim", "Yuriy Lvovich Orlov", "Le Yau Yit", "Henry Yang", "Lay Teng Ang", "Lorenz Poellinger", "Bing Lim"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1002130.s001", "https://dx.doi.org/10.1371/journal.pgen.1002130.s002", "https://dx.doi.org/10.1371/journal.pgen.1002130.s003", "https://dx.doi.org/10.1371/journal.pgen.1002130.s004", "https://dx.doi.org/10.1371/journal.pgen.1002130.s005", "https://dx.doi.org/10.1371/journal.pgen.1002130.s006", "https://dx.doi.org/10.1371/journal.pgen.1002130.s007", "https://dx.doi.org/10.1371/journal.pgen.1002130.s008", "https://dx.doi.org/10.1371/journal.pgen.1002130.s009", "https://dx.doi.org/10.1371/journal.pgen.1002130.s010"], "stats"=>{"downloads"=>13, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Graded_Nodal_Activin_Signaling_Titrates_Conversion_of_Quantitative_Phospho_Smad2_Levels_into_Qualitative_Embryonic_Stem_Cell_Fate_Decisions/135708", "title"=>"Graded Nodal/Activin Signaling Titrates Conversion of Quantitative Phospho-Smad2 Levels into Qualitative Embryonic Stem Cell Fate Decisions", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-06-23 01:35:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/763519"], "description"=>"<p>UCSC Genome Browser representation of pSmad2 enrichment peaks under Activin (red), DMSO control (blue) and SB (green) signaling conditions in ES cells. Genomic locations of signaling regulated peaks correspond to (A) graded binding to intron of <i>Radil</i> in all 3 conditions, (B) discrete binding to promoter and exon of <i>Id1</i> specific to SB treatment, (C) binding to the 3′ region of <i>2210011C2Rik</i> only in the Activin condition and (D) multimodal recruitment of pSmad2 in ChIP-Seq peaks marked with (*) where it is SB specific in the promoter region of <i>Copz2</i> and graded in correlation with signaling in the intronic region. All target genes were identified to be differentially expressed under the 3 signaling conditions in the microarray analysis of <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002130#pgen-1002130-g003\" target=\"_blank\">Figure 3A</a>. Top panels show raw sequencing tag enrichments in Activin/DMSO/SB on the vertical axis. Bottom panels show ChIP-Seq peak positions and intensities defined by the MACS program based on normalization to the respective input DNA sequencing controls for each condition. Horizontal scale shows genomic coordinates on the indicated chromosomes and scale bar denotes genomic distance. Structure of the indicated target genes is represented by thick solid lines for exons, thin solid lines for UTRs and continuous arrows running from 5′ to 3′ for introns.</p>", "links"=>[], "tags"=>["signaling", "multimodal", "modes", "phospho-smad2"], "article_id"=>433887, "categories"=>["Molecular Biology", "Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Kian Leong Lee", "Sandy Keat Lim", "Yuriy Lvovich Orlov", "Le Yau Yit", "Henry Yang", "Lay Teng Ang", "Lorenz Poellinger", "Bing Lim"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002130.g006", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Graded_Low_Signaling_Dominant_High_Signaling_Dominant_and_Multimodal_Modes_of_Phospho_Smad2_Target_Gene_Binding_/433887", "title"=>"Graded, Low Signaling Dominant, High Signaling Dominant, and Multimodal Modes of Phospho-Smad2 Target Gene Binding.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-06-23 01:04:47"}

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