Genome-wide strategies identify downstream target genes of connective tissue-associated transcription factors
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ABSTRACT:
ORGANISM(S): Gallus gallus
PROVIDER: GSE100517 | GEO | 2017/07/19
SECONDARY ACCESSION(S): PRJNA391992
REPOSITORIES: GEO
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Project description:Connective tissues support organs and play crucial roles in development, homeostasis and fibrosis, yet our understanding of their formation is still limited. To gain insight into the molecular mechanisms of connective tissue specification, we selected five zinc finger transcription factors - OSR1, OSR2, EGR1, KLF2 and KLF4 - based on their expression patterns and/or known involvement in connective tissue subtype differentiation. RNA-seq and ChIP-seq profiling revealed a set of common genes regulated by all five transcription factors, which we propose as connective tissue core expression set. This common core was enriched in genes associated with axon guidance and myofibroblast signature, including fibrosis-related genes. In addition, each transcription factor regulated a specific set of signalling molecules and extracellular matrix components. This suggests a concept whereby local molecular niches can be created via the expression of specific transcription factors impinging on the specification of local microenvironments. The regulatory network established here identifies common and distinct molecular signatures of limb connective tissue subtypes, provides novel insight into the signalling pathways governing connective tissue specification, and serves as a resource for connective tissue development.
2017-07-19 | GSE100516 | GEO
Project description:Connective tissues support organs and play crucial roles in development, homeostasis and fibrosis, yet our understanding of their formation is still limited. To gain insight into the molecular mechanisms of connective tissue specification, we selected five zinc finger transcription factors - OSR1, OSR2, EGR1, KLF2 and KLF4 - based on their expression patterns and/or known involvement in connective tissue subtype differentiation. RNA-seq and ChIP-seq profiling revealed a set of common genes regulated by all five transcription factors, which we propose as connective tissue core expression set. This common core was enriched in genes associated with axon guidance and myofibroblast signature, including fibrosis-related genes. In addition, each transcription factor regulated a specific set of signalling molecules and extracellular matrix components. This suggests a concept whereby local molecular niches can be created via the expression of specific transcription factors impinging on the specification of local microenvironments. The regulatory network established here identifies common and distinct molecular signatures of limb connective tissue subtypes, provides novel insight into the signalling pathways governing connective tissue specification, and serves as a resource for connective tissue development.
2017-07-19 | GSE100515 | GEO
Project description:Connective tissues support organs and play crucial roles in development, homeostasis and fibrosis, yet our understanding of their formation is still limited. To gain insight into the molecular mechanisms of connective tissue specification, we selected five zinc finger transcription factors - OSR1, OSR2, EGR1, KLF2 and KLF4 - based on their expression patterns and/or known involvement in connective tissue subtype differentiation. RNA-seq and ChIP-seq profiling revealed a set of common genes regulated by all five transcription factors, which we propose as connective tissue core expression set. This common core was enriched in genes associated with axon guidance and myofibroblast signature, including fibrosis-related genes. In addition, each transcription factor regulated a specific set of signalling molecules and extracellular matrix components. This suggests a concept whereby local molecular niches can be created via the expression of specific transcription factors impinging on the specification of local microenvironments. The regulatory network established here identifies common and distinct molecular signatures of limb connective tissue subtypes, provides novel insight into the signalling pathways governing connective tissue specification, and serves as a resource for connective tissue development.
2017-07-19 | GSE100514 | GEO
Project description:Genome-wide strategies identify downstream target genes of connective tissue-associated transcription factors
| PRJNA391992 | ENA
Project description:Background: The distribution and composition of cis-regulatory modules composed of transcription factor (TF) binding site (TFBS) clusters in promoters substantially determine gene expression patterns and TF targets. TF knockdown experiments have revealed that TF binding profiles and gene expression levels are correlated. We use TFBS features within accessible promoter intervals to predict genes with similar tissue-wide expression patterns and TF targets using Machine Learning (ML). Methods: Bray-Curtis Similarity was used to identify genes with correlated expression patterns across 53 tissues. TF targets from knockdown experiments were also analyzed by this approach to set up the ML framework. TFBSs were selected within DNase I-accessible intervals of corresponding promoter sequences using information theory-based position weight matrices (iPWMs) for each TF. Features from information-dense clusters of TFBSs were input to ML classifiers which predict these gene targets along with their accuracy, specificity and sensitivity. Mutations in TFBSs were analyzed in silico to examine their impact on TFBS clustering and predict changes in gene regulation. Results: The glucocorticoid receptor gene ( NR3C1), whose regulation has been extensively studied, was selected to test this approach. SLC25A32 and TANK exhibited the most similar expression patterns to NR3C1. A Decision Tree classifier exhibited the best performance in detecting such genes, based on Area Under the Receiver Operating Characteristic curve (ROC). TF target gene prediction was confirmed using siRNA knockdown, which was more accurate than CRISPR/CAS9 inactivation. TFBS mutation analyses revealed that accurate target gene prediction required at least 1 information-dense TFBS cluster. Conclusions: ML based on TFBS information density, organization, and chromatin accessibility accurately identifies gene targets with comparable tissue-wide expression patterns. Multiple information-dense TFBS clusters in promoters appear to protect promoters from effects of deleterious binding site mutations in a single TFBS that would otherwise alter regulation of these genes.
| S-EPMC6464064 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-05-20 | GSE130202 | GEO
Project description:The development of a vascular network is essential to nourish tissues and sustain organ function throughout life. Endothelial cells (ECs) are the building blocks of blood vessels, yet our understanding of EC specification in vertebrates remains incomplete. cloche/npas4l mutants have broadly been used as an avascular model in zebrafish, but little is known about the molecular mechanism of action of Npas4l. Here, to identify the direct and indirect target genes of this transcription factor, we combined complementary genome-wide approaches, including transcriptome analyses and chromatin immunoprecipitation (ChIP). The cross-analysis of these datasets indicate that Npas4l functions as a master regulator by directly inducing a wave of transcription factor genes crucial for hematoendothelial specification in vertebrates, including etv2, tal1, and lmo2. We identified additional target genes acting downstream of npas4l and investigated the function of a subset of them using CRISPR/Cas9 technology. Phenotypic characterization of tspan18b mutants reveals a novel role for tspan18b in developmental angiogenesis, confirming the reliability of the datasets generated. Collectively, these data represent a useful resource for future studies aimed to investigate novel genes with a potential role in vascular development and EC fate determination in vertebrates.
2019-05-21 | GSE130198 | GEO
Project description:The development of a vascular network is essential to nourish tissues and sustain organ function throughout life. Endothelial cells (ECs) are the building blocks of blood vessels, yet our understanding of EC specification in vertebrates remains incomplete. cloche/npas4l mutants have broadly been used as an avascular model in zebrafish, but little is known about the molecular mechanism of action of Npas4l. Here, to identify the direct and indirect target genes of this transcription factor, we combined complementary genome-wide approaches, including transcriptome analyses and chromatin immunoprecipitation (ChIP). The cross-analysis of these datasets indicate that Npas4l functions as a master regulator by directly inducing a wave of transcription factor genes crucial for hematoendothelial specification in vertebrates, including etv2, tal1, and lmo2. We identified additional target genes acting downstream of npas4l and investigated the function of a subset of them using CRISPR/Cas9 technology. Phenotypic characterization of tspan18b mutants reveals a novel role for tspan18b in developmental angiogenesis, confirming the reliability of the datasets generated. Collectively, these data represent a useful resource for future studies aimed to investigate novel genes with a potential role in vascular development and EC fate determination in vertebrates.
2019-05-21 | GSE130196 | GEO
Project description:Insulin analogs were developed to improve diabetes therapy. However, certain modifications introduced into the insulin molecule were shown to enhance their affinity to the insulin-like growth factor-1 receptor (IGF1R). Most tumors, including endometrial cancers, express high levels of IGF1R. The present study was aimed at identifying the entire set of genes that are differentially activated by insulin glargine or detemir, in comparison to insulin and IGF1, in Type 1 and Type 2 endometrial cancer cell lines (ECC-1 and USPC-1, respectively). Global gene expression analyses demonstrated a ligand-dependent upregulated expression of filamin-A (FLNA), a gene that encodes an actin filament cross-linking protein, in both endometrial cancer cell types. Silencing experiments linked to migration assays confirmed the role of FLNA in cell growth and motility. Our data suggest that the activation of distinct sets of genes by glargine may lead to stimulation of specific pathways or, alternatively, may provide additive effects, different from those classically induced by insulin. Given that metastases are probably the main factor contributing to tumor invasiveness, the identification of FLNA as a downstream target for insulin-like hormones may be of translational relevance in oncology. Clinical studies in endometrial cancer may add further relevant information regarding the possible differential actions of insulin analogs with respect to native insulin.
| S-EPMC5870203 | biostudies-literature
Project description:The development of a vascular network is essential to nourish tissues and sustain organ function throughout life. Endothelial cells (ECs) are the building blocks of blood vessels, yet our understanding of EC specification in vertebrates remains incomplete. cloche/npas4l mutants have broadly been used as an avascular model in zebrafish, but little is known about the molecular mechanism of action of Npas4l. Here, to identify the direct and indirect target genes of this transcription factor, we combined complementary genome-wide approaches, including transcriptome analyses and chromatin immunoprecipitation (ChIP). The cross-analysis of these datasets indicate that Npas4l functions as a master regulator by directly inducing a wave of transcription factor genes crucial for hematoendothelial specification in vertebrates, including etv2, tal1, and lmo2. We identified additional target genes acting downstream of npas4l and investigated the function of a subset of them using CRISPR/Cas9 technology. Phenotypic characterization of tspan18b mutants reveals a novel role for tspan18b in developmental angiogenesis, confirming the reliability of the datasets generated. Collectively, these data represent a useful resource for future studies aimed to investigate novel genes with a potential role in vascular development and EC fate determination in vertebrates.
2019-05-21 | GSE130199 | GEO