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Responsiveness of genes to manipulation of transcription factors in ES cells is associated with chromatin structure and tissue specificity

ABSTRACT: Background: In addition to determining static states of gene expression (high vs. low), it is important to characterize their dynamic status. For example, genes with H3K27me3 chromatin marks are not only suppressed but also poised for activation. However, the responsiveness of genes to perturbations has never been studied systematically. To distinguish gene responses to specific factors from responsiveness in general, it is necessary to analyze gene expression profiles of cells responding to a large variety of disturbances, and such databases did not exist before. Results: We estimated the responsiveness of all genes in mouse ES cells using our recently published database on expression change after controlled induction of 53 transcription factors (TFs) and other genes. Responsive genes (/N/ = 4746), which were readily upregulated or downregulated depending on the kind of perturbation, mostly have regulatory functions and a propensity to become tissue-specific upon differentiation. Tissue-specific expression was evaluated on the basis of published (GNF) and our new data for 15 organs and tissues. Non-responsive genes (/N/ = 9562), which did not change their expression much following any perturbation, were enriched in housekeeping functions. We found that TF-responsiveness in ES cells is the best predictor known for tissue-specificity in gene expression. Among genes with CpG islands, high responsiveness is strongly associated with H3K27me3 chromatin marks, and low responsiveness is associated with H3K36me3 chromatin, binding of E2F1, and GABP binding motifs in promoters. Conclusions: We thus propose the responsiveness of expression to perturbations as a new way to define the dynamic status of genes, which brings new insights into mechanisms of regulation of gene expression and tissue specificity. This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE22151 | GEO | 2011/02/14

SECONDARY ACCESSION(S): PRJNA127711

REPOSITORIES: GEO

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Project description:Background: In addition to determining static states of gene expression (high vs. low), it is important to characterize their dynamic status. For example, genes with H3K27me3 chromatin marks are not only suppressed but also poised for activation. However, the responsiveness of genes to perturbations has never been studied systematically. To distinguish gene responses to specific factors from responsiveness in general, it is necessary to analyze gene expression profiles of cells responding to a large variety of disturbances, and such databases did not exist before. Results: We estimated the responsiveness of all genes in mouse ES cells using our recently published database on expression change after controlled induction of 53 transcription factors (TFs) and other genes. Responsive genes (/N/ = 4746), which were readily upregulated or downregulated depending on the kind of perturbation, mostly have regulatory functions and a propensity to become tissue-specific upon differentiation. Tissue-specific expression was evaluated on the basis of published (GNF) and our new data for 15 organs and tissues. Non-responsive genes (/N/ = 9562), which did not change their expression much following any perturbation, were enriched in housekeeping functions. We found that TF-responsiveness in ES cells is the best predictor known for tissue-specificity in gene expression. Among genes with CpG islands, high responsiveness is strongly associated with H3K27me3 chromatin marks, and low responsiveness is associated with H3K36me3 chromatin, binding of E2F1, and GABP binding motifs in promoters. Conclusions: We thus propose the responsiveness of expression to perturbations as a new way to define the dynamic status of genes, which brings new insights into mechanisms of regulation of gene expression and tissue specificity. This SuperSeries is composed of the following subset Series: GSE19806: Responsiveness of genes to manipulation of transcription factors in ES cells is associated with histone modifications and tissue specificity (1 of 2) GSE19814: Responsiveness of genes to manipulation of transcription factors in ES cells is associated with histone modifications and tissue specificity (2 of 2) Refer to individual Series

Project description:BACKGROUND: In addition to determining static states of gene expression (high vs. low), it is important to characterize their dynamic status. For example, genes with H3K27me3 chromatin marks are not only suppressed but also poised for activation. However, the responsiveness of genes to perturbations has never been studied systematically. To distinguish gene responses to specific factors from responsiveness in general, it is necessary to analyze gene expression profiles of cells responding to a large variety of disturbances, and such databases did not exist before. RESULTS: We estimated the responsiveness of all genes in mouse ES cells using our recently published database on expression change after controlled induction of 53 transcription factors (TFs) and other genes. Responsive genes (N = 4746), which were readily upregulated or downregulated depending on the kind of perturbation, mostly have regulatory functions and a propensity to become tissue-specific upon differentiation. Tissue-specific expression was evaluated on the basis of published (GNF) and our new data for 15 organs and tissues. Non-responsive genes (N = 9562), which did not change their expression much following any perturbation, were enriched in housekeeping functions. We found that TF-responsiveness in ES cells is the best predictor known for tissue-specificity in gene expression. Among genes with CpG islands, high responsiveness is associated with H3K27me3 chromatin marks, and low responsiveness is associated with H3K36me3 chromatin, stronger tri-methylation of H3K4, binding of E2F1, and GABP binding motifs in promoters. CONCLUSIONS: We thus propose the responsiveness of expression to perturbations as a new way to define the dynamic status of genes, which brings new insights into mechanisms of regulation of gene expression and tissue specificity. Total RNA was isolated by TRIzol (Invitrogen) after 2 days. Cy3-CTP labeled sample targets were prepared with total RNA by Low RNA Input Fluorescent Linear Amplification Kit (Agilent). Cy5-CTP labeled reference target was produced from mixture of Stratagene Universal Mouse Reference RNA and MC1 cells RNA. Most samples were collected in 2 replications taken from different animals, except bone and fat, which had only one replication.

Project description:BACKGROUND: In addition to determining static states of gene expression (high vs. low), it is important to characterize their dynamic status. For example, genes with H3K27me3 chromatin marks are not only suppressed but also poised for activation. However, the responsiveness of genes to perturbations has never been studied systematically. To distinguish gene responses to specific factors from responsiveness in general, it is necessary to analyze gene expression profiles of cells responding to a large variety of disturbances, and such databases did not exist before. RESULTS: We estimated the responsiveness of all genes in mouse ES cells using our recently published database on expression change after controlled induction of 53 transcription factors (TFs) and other genes. Responsive genes (N = 4746), which were readily upregulated or downregulated depending on the kind of perturbation, mostly have regulatory functions and a propensity to become tissue-specific upon differentiation. Tissue-specific expression was evaluated on the basis of published (GNF) and our new data for 15 organs and tissues. Non-responsive genes (N = 9562), which did not change their expression much following any perturbation, were enriched in housekeeping functions. We found that TF-responsiveness in ES cells is the best predictor known for tissue-specificity in gene expression. Among genes with CpG islands, high responsiveness is associated with H3K27me3 chromatin marks, and low responsiveness is associated with H3K36me3 chromatin, stronger tri-methylation of H3K4, binding of E2F1, and GABP binding motifs in promoters. CONCLUSIONS: We thus propose the responsiveness of expression to perturbations as a new way to define the dynamic status of genes, which brings new insights into mechanisms of regulation of gene expression and tissue specificity Inhibitors of cell signaling are known to support the pluripotent state of embryonic stem cells (Ying et al. 2008, Nature 453, 519-523, PMID: 18497825). To characterize the effect of inhibitors on the gene expression we treated B6R(5) mouse ES cells (C57BL/6 strain) with FGFR inhibitor PD173074 (100 uM), MEK inhibitor PD98059 (25 uM),and GSK-3 inhibitor BIO (2 uM) 24 hr after plating. Cells were grown without feeders on gelatin coated, 6-well plates, 100,000 cells/well (10^4 cells/cm2), in complete ES medium at 37 0C; 5% CO2. Medium was changed daily. Inhibitors dissolved in DMSO were added 24 hr after plating and cells were harvested 48 hr after treatment (72 hr after plating). Control cells were treated with DMSO. Keywords: cell type comparison design,reference design Total RNA was isolated by TRIzol (Invitrogen) after 2 days. Cy3-CTP labeled sample targets were prepared with total RNA by Low RNA Input Fluorescent Linear Amplification Kit (Agilent). Cy5-CTP labeled reference target was Stratagene Universal Mouse Reference RNA.

Project description:BACKGROUND: In addition to determining static states of gene expression (high vs. low), it is important to characterize their dynamic status. For example, genes with H3K27me3 chromatin marks are not only suppressed but also poised for activation. However, the responsiveness of genes to perturbations has never been studied systematically. To distinguish gene responses to specific factors from responsiveness in general, it is necessary to analyze gene expression profiles of cells responding to a large variety of disturbances, and such databases did not exist before. RESULTS: We estimated the responsiveness of all genes in mouse ES cells using our recently published database on expression change after controlled induction of 53 transcription factors (TFs) and other genes. Responsive genes (N = 4746), which were readily upregulated or downregulated depending on the kind of perturbation, mostly have regulatory functions and a propensity to become tissue-specific upon differentiation. Tissue-specific expression was evaluated on the basis of published (GNF) and our new data for 15 organs and tissues. Non-responsive genes (N = 9562), which did not change their expression much following any perturbation, were enriched in housekeeping functions. We found that TF-responsiveness in ES cells is the best predictor known for tissue-specificity in gene expression. Among genes with CpG islands, high responsiveness is associated with H3K27me3 chromatin marks, and low responsiveness is associated with H3K36me3 chromatin, stronger tri-methylation of H3K4, binding of E2F1, and GABP binding motifs in promoters. CONCLUSIONS: We thus propose the responsiveness of expression to perturbations as a new way to define the dynamic status of genes, which brings new insights into mechanisms of regulation of gene expression and tissue specificity Inhibitors of cell signaling are known to support the pluripotent state of embryonic stem cells (Ying et al. 2008, Nature 453, 519-523, PMID: 18497825). To characterize the effect of inhibitors on the gene expression we treated B6R(5) mouse ES cells (C57BL/6 strain) with FGFR inhibitor PD173074 (100 uM), MEK inhibitor PD98059 (25 uM),and GSK-3 inhibitor BIO (2 uM) 24 hr after plating. Cells were grown without feeders on gelatin coated, 6-well plates, 100,000 cells/well (10^4 cells/cm2), in complete ES medium at 37 0C; 5% CO2. Medium was changed daily. Inhibitors dissolved in DMSO were added 24 hr after plating and cells were harvested 48 hr after treatment (72 hr after plating). Control cells were treated with DMSO. Keywords: cell type comparison design,reference design

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Responsiveness of genes to manipulation of transcription factors in ES cells is associated with chromatin structure and tissue specificity

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