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Olig1 is a Smad cofactor involved in cell motility induced by transforming growth factor-b

ABSTRACT: Transforming growth factor (TGF)-β plays crucial roles in embryonic development and adult tissue homeostasis by eliciting various cellular responses in target cells. TGF-β signaling is principally mediated through receptor-activated Smad proteins, which regulate expression of target genes in cooperation with other DNA-binding transcriptionfactors (Smad cofactors). In this study, we found that the basic helix-loop-helix transcription factor Olig1 is a Smad cofactor involved in TGF-b-induced cell motility. Knockdown of Olig1 attenuated TGF-β-induced cell motility in chamber migration and wound healing assays. In contrast, Olig1 knockdown had no effect on bone morphogenetic protein-induced cell motility, TGF-β-induced cytostasis or epithelial-mesenchymal transition. Furthermore, we observed that cooperation of Smad2/3 with Olig1 is regulated by a peptidyl-prolyl cis/trans isomerase, Pin1. TGF-b-induced cell motility, induction of Olig1-regulated genes, and physical interaction between Smad2/3 and Olig1 were all inhibited after knockdown of Pin1, indicating a novel mode of regulation of Smad signaling. We also found that Olig1 interacts with the L3 loop of Smad3. Using a synthetic peptide corresponding to the L3 loop of Smad3, we succeeded in selectively inhibiting TGF-b-induced cell motility. These findings may lead to a new strategy for selective regulation of TGF-b-induced cellular responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE46405 | GEO | 2013/07/01

SECONDARY ACCESSION(S): PRJNA200284

REPOSITORIES: GEO

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Olig1 is a Smad cofactor involved in cell motility induced by transforming growth factor-b

Project description:Transforming growth factor (TGF)-Î² plays crucial roles in embryonic development and adult tissue homeostasis by eliciting various cellular responses in target cells. TGF-Î² signaling is principally mediated through receptor-activated Smad proteins, which regulate expression of target genes in cooperation with other DNA-binding transcriptionfactors (Smad cofactors). In this study, we found that the basic helix-loop-helix transcription factor Olig1 is a Smad cofactor involved in TGF-b-induced cell motility. Knockdown of Olig1 attenuated TGF-Î²-induced cell motility in chamber migration and wound healing assays. In contrast, Olig1 knockdown had no effect on bone morphogenetic protein-induced cell motility, TGF-Î²-induced cytostasis or epithelial-mesenchymal transition. Furthermore, we observed that cooperation of Smad2/3 with Olig1 is regulated by a peptidyl-prolyl cis/trans isomerase, Pin1. TGF-b-induced cell motility, induction of Olig1-regulated genes, and physical interaction between Smad2/3 and Olig1 were all inhibited after knockdown of Pin1, indicating a novel mode of regulation of Smad signaling. We also found that Olig1 interacts with the L3 loop of Smad3. Using a synthetic peptide corresponding to the L3 loop of Smad3, we succeeded in selectively inhibiting TGF-b-induced cell motility. These findings may lead to a new strategy for selective regulation of TGF-b-induced cellular responses. NMuMG cells were transfected with siRNAs (siControl, siOlig1 or siPin1) and treated with or without TGF-b for 1h. We compared genes affected by knockdown of Olig1 and that of Pin1.

2013-07-01 | E-GEOD-46405 | biostudies-arrayexpress

Long noncoding RNA ELIT-1 acts as a Smad3 cofactor to facilitate TGF-β/Smad signaling and promote epithelial-mesenchymal transition

Project description:TGF-β is involved in various biological processes, including development, differentiation, growth regulation, and epithelial-mesenchymal transition (EMT). In TGF-β/Smad signaling, receptor-activated Smad complexes activate or repress their target gene promoters. Smad cofactors are a group of Smad-binding proteins that promote recruitment of Smad complexes to these promoters. Long noncoding RNAs (lncRNAs), that behave as Smad cofactors have thus far not been identified. Here, we characterize a novel lncRNA EMT-associated lncRNA induced by TGF-β-1(ELIT-1). ELIT-1 was induced by TGF-β-stimulation via the TGF-β/Smad pathway in TGF-β-responsive cell lines. ELIT-1-depletion abrogated TGF-β-mediated EMT progression and expression of TGF-β target genes including Snail, a transcription factor critical for EMT. A positive correlation between high expression of ELIT-1 and poor prognosis in lung adenocarcinoma and gastric cancer patients suggests that ELIT-1 may be useful as a prognostic and therapeutic target. RIP assays revealed that ELIT-1 bound to Smad3, but not Smad2. In conjunction with Smad3, ELIT-1 enhanced Smad-responsive promoter activities by recruiting Smad3 to the promoters of its target genes including Snail, other TGF-β-target genes, and ELIT-1 itself. Collectively, these data show that ELIT-1 is a novel trans-acting lncRNA that forms a positive feedback loop to enhance TGF-β/Smad3 signaling and promote EMT progression.

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Long noncoding RNA ELIT-1 acts as a Smad3 cofactor to facilitate TGF-β/Smad signaling and promote epithelial-mesenchymal transition

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HNF4A-binding sites in HepG2 hepatoblastoma cells treated with TGF-beta

Project description:Specific regulation of target genes by transforming growth factor-β (TGF-β) in a given cellular context is determined in part by transcription factors and cofactors that interact with the Smad complex. In the present study, we determined Smad2 and Smad3 (Smad2/3) binding regions in the promoters of known genes in HepG2 hepatoblastoma cells, and compared them to those in HaCaT epidermal keratinocytes to elucidate the mechanisms of cell type- and context-dependent regulation of transcription induced by TGF-β. Our results show that 81% of the Smad2/3 binding regions in HepG2 cells were not shared with those found in HaCaT cells. Hepatocyte nuclear factor 4α (HNF4α) is expressed in HepG2 cells, but not in HaCaT cells, and the HNF4α binding motif was identified as an enriched motif in the HepG2-specific Smad2/3 binding regions. ChIP-sequencing analysis of HNF4A binding regions under TGF-β stimulation revealed that 32.5% of the Smad2/3 binding regions overlapped HNF4A bindings. MIXL1 was identified as a new combinatorial target of HNF4A and Smad2/3, and both the HNF4A protein and its binding motif were required for the induction of MIXL1 by TGF-β in HepG2 cells. These findings generalize the importance of binding of HNF4A on Smad2/3 binding genomic regions for HepG2-specific regulation of transcription by TGF-β, and suggest that certain transcription factors expressed in a cell-type-specific manner play important roles in the transcription regulated by the TGF-β-Smad signaling pathway. HepG2 cells were treated with TGF-beta for 1.5 h or left untreated. anti-HNF4A ChIP-seq was performed. One lane was used for each sample.

2011-06-08 | E-GEOD-28845 | biostudies-arrayexpress

RNA-seq in human progenitor epidermal keratinocytes (HPEK) stimulated with TGF-beta.

Project description:Smad family proteins transduce signals downstream of transforming growth factor-beta (TGF-beta) and are one of the factors that regulate target genes related to diseases affecting the skin. We here identified C2orf54, officially known as MAB21L4, as one of the most up-regulated targets of TGF-beta and Smad3 in a differentiated human progenitor epidermal keratinocyte, using chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq). Smad2 and Smad3 bind to the regulatory regions of the C2orf54 gene locus. We found that TGF-beta induced expression of a barrier protein involucrin (encoded by IVL gene), and transcriptional activity of the IVL promoter induced by TGF-beta was inhibited by siRNAs for C2orf54. Further analysis revealed that C2orf54 siRNAs also down-regulated the expression of several target genes of TGF-beta. C2orf54 protein located mainly in the cytosol, physically bound to Smad2 and Smad3, but did not inhibit the binding of Smad2 and Smad3 to the target genomic regions. These findings suggested that TGF-beta-induced C2orf54 up-regulates gene expression induced by Smads, possibly through its physical interaction with Smad proteins.

2021-12-16 | GSE180251 | GEO

Smad3 binding regions in differentiated human progenitor epidermal keratinocytes (HPEK).

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Transcription profiling timecourse of induced DACH1 expression in a human breast cancer cell line

Project description:The vertebrate homologues of Drosophila dachsund, DACH1 and DACH2, have been implicated as important regulatory genes in development. DACH1 plays a role in retinal and pituitary precursor cell proliferation and DACH2 plays a specific role in myogenesis. DACH proteins contain a domain (DS-domain) that is conserved with the proto-oncogenes Ski and Sno. Since the Ski/Sno proto-oncogenes repress AP-1 and SMAD signaling, we hypothesized that DACH1 might play a similar cellular function. Herein, DACH1 was found to be expressed in breast cancer cell lines and to inhibit TGF-beta induced apoptosis. DACH1 repressed TGF-beta induction of AP-1 and Smad signaling in gene reporter assays and repressed endogenous TGF-beta responsive genes by microarray analyses. DACH1 bound to endogenous NCoR and Smad4 in cultured cells and DACH1 co-localized with NCoR in nuclear dot-like structures. NCoR enhanced DACH1 repression and the repression of TGF-beta-induced AP-1 or Smad-signaling by DACH1 required the DACH1 DS domain. The DS-domain of DACH was sufficient for NCoR-binding at a Smad4-binding site. Smad4 was required for DACH1 repression of Smad signaling. In Smad4 null HTB-134 cells, DACH1 inhibited the activation of SBE-4 reporter activity induced by Smad2 or Smad3 only in the presence of Smad4. DACH1 participates in the negative regulation of TGF-beta signaling by interacting with NCoR and Smad4.

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HNF4A-binding sites in HepG2 hepatoblastoma cells treated with TGF-beta

2011-06-08 | GSE28845 | GEO

Smad2/3 binding regions in NMuMG cells

Project description:Smad2/3 binding regions in mouse mammary gland epithelial cells (NMuMG) treated with TGF-beta for 1.5 h were determined by ChIP-seq to evaluate the transcriptional mechanism of TGF-beta-Smad signaling.

2019-08-29 | GSE121254 | GEO

Smad2/3 binding sites in HaCaT, HepG2, and Hep3B cells determined by an Affymetrix promoter array

Project description:Specific regulation of target genes by transforming growth factor-β (TGF-β) in a given cellular context is determined in part by transcription factors and cofactors that interact with the Smad complex. In the present study, we determined Smad2 and Smad3 (Smad2/3) binding regions in the promoters of known genes in HepG2 hepatoblastoma cells, and compared them to those in HaCaT epidermal keratinocytes to elucidate the mechanisms of cell-type- and context-dependent regulation of transcription induced by TGF-β. Our results show that 81% of the Smad2/3 binding regions in HepG2 cells were not shared with those found in HaCaT cells. Hepatocyte nuclear factor 4α (HNF4α) is expressed in HepG2 cells, but not in HaCaT cells, and the HNF4α binding motif was identified as an enriched motif in the HepG2-specific Smad2/3 binding regions. ChIP-sequencing analysis of HNF4α binding regions under TGFα stimulation revealed that 32.5% of the Smad2/3 binding regions overlapped HNF4α bindings. MIXL1 was identified as a new combinatorial target of HNF4α and Smad2/3, and both the HNF4α protein and its binding motif were required for the induction of MIXL1 by TGF-β in HepG2 cells. These findings generalize the importance of binding of HNF4α on Smad2/3 binding genomic regions for HepG2-specific regulation of transcription by TGF-β, and suggest that certain transcription factors expressed in a cell-type-specific manner play important roles in the transcription regulated by the TGF-β-Smad signaling pathway.

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