Transcription Factor p73 Regulates Th1 Differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA603788 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10987090.fastq.gz | Fastqsanger.gz | |||
| SRR10987091.fastq.gz | Fastqsanger.gz | |||
| SRR10987092.fastq.gz | Fastqsanger.gz | |||
| SRR10987093.fastq.gz | Fastqsanger.gz | |||
| SRR10987094.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
Similar Datasets
Project description:Transcription Factor p73 Regulates Th1 Differentiation
| PRJNA419910 | ENA
Project description:Inter-individual differences in T helper (Th) cell responses affect susceptibility to infectious, allergic, and autoimmune diseases. To identify factors contributing to these response differences, we analyzed the phenotypic profiles of in vitro-differentiated Th1 cells from 16 inbred mouse strains. Haplotype-based computational genetic analysis indicated that the p53 family protein, p73, affected Th1 differentiation. In cells differentiated under Th1 conditions in vitro, we demonstrated that p73 was a negative regulator of IFNγ production, and this effect required the DNA-binding activity of p73. p73 bound within the gene body or upstream of many genes that affect Th1 differentiation and regulated their expression (e.g., Ifng and Il12rb2). Furthermore, in experimental autoimmune encephalitis, which is a mouse disease model of multiple sclerosis, p73-deficient mice had increased IFNg production and decreased disease severity, whereas in the adoptive transfer model of inflammatory bowel disease, transfer of p73- deficient naïve CD4+ T cells into WT Rag2-/- hosts resulted in increased Th1 responses and enhanced disease severity compared to transfer of WT cells. These studies identify p73 as a regulator of immune responses and indicate that its dysregulation may play a role in susceptibility to autoimmune disease.
2020-01-29 | GSE144496 | GEO
Project description:T helper (Th) cells play critical functions in response to infectious, allergic, and autoimmune diseases. Upon exposure to a given infectious agent or stimulus, different individuals vary in their Th cell responses, influencing the final disease outcome. To investigate the genetic factors that contribute to such differential immune responses, we performed a haplotype-based computational genetic analysis based on the phenotypic profiles of in vitro differentiated Th1 cells from 16 inbred mouse strains. And we identified genes including that encoding the p53 family protein, p73, with SNP patterns that correlated with the quantitative difference in IFNγ expression. Overexpression of p73 inhibited Th1 differentiation, as evaluated by reduced IFNγ expression, whereas shRNA knockdown or knockout of the p73 gene augmented IFNγ production. An inhibitory effect of p73 on Th1 differentiation was also observed in Stat1-/- cells, indicating that the effect was at least partially independent of STAT1. The DNA-binding activity of p73 is required for its inhibitory effect on IFNγ expression, as deletion of p73 DNA binding domain abolished IFNγ inhibition. A global gene expression analysis showed that 206 genes are differentially expressed more than two-fold in response to p73 overexpression, and 55 of these are direct target genes of p73 in Th1 cells, based on ChIP-seq analysis. p73 binding peaks were identified at a range of genes, including at the Il12rb2, Il24, and Il2ra loci, and p73 was implicated for regulating these genes based on reporter constructs containing WT or mutant p73 binding sites. Furthermore, p73 deficient mice had reduced disease severity in MOG induced EAE, with increased IFNg production from spinal cord infiltrating cells. Thus, p73 is a novel regulator of IFNγ expression, revealing a previously unanticipated role for p73 in Th1 cell differentiation.
2019-12-18 | GSE107368 | GEO
Project description:Inter-individual differences in T helper (Th) cell responses affect susceptibility to infectious, allergic and autoimmune diseases. To identify factors contributing to these response differences, here we analyze in vitro differentiated Th1 cells from 16 inbred mouse strains. Haplotype-based computational genetic analysis indicates that the p53 family protein, p73, affects Th1 differentiation. In cells differentiated under Th1 conditions in vitro, p73 negatively regulates IFNγ production. p73 binds within, or upstream of, and modulates the expression of Th1 differentiation-related genes such as Ifng and Il12rb2. Furthermore, in mouse experimental autoimmune encephalitis, p73-deficient mice have increased IFNγ production and less disease severity, whereas in an adoptive transfer model of inflammatory bowel disease, transfer of p73-deficient naïve CD4+ T cells increases Th1 responses and augments disease severity. Our results thus identify p73 as a negative regulator of the Th1 immune response, suggesting that p73 dysregulation may contribute to susceptibility to autoimmune disease.
| S-EPMC7081339 | biostudies-literature
Project description:The p53 homologue, p63, is critical for normal epidermal development. While overexpression of deltaNp63alpha has been reported in squamous cell cancers, the contribution of p63 to cancer pathogenesis remains unclear. We previously demonstrated that overexpressed deltaNp63alpha aberrantly maintains proliferation of primary epidermal keratinocytes under conditions that normally induce growth arrest and differentiation. To identify target genes impacted by dysregulated deltaNp63alpha that may contribute to squamous cancer development and progression, microarray analyses were performed. Herein we report that elevated deltaNp63alpha differentially regulates genes in primary mouse keratinocytes involved in a variety of cellular functions, including cell cycle regulation, differentiation, skin barrier formation and function, apoptosis, host defense/inflammation, adhesion, migration and invasion. Of note, multiple protease inhibitor mRNAs were coordinately downregulated under both proliferating and differentiating culture conditions. These downregulated genes include two serine protease inhibitors: maspin (serpinB5) and plasminogen activator inhibitor-2 (PAI-2; serpinB2), as well as a tissue inhibitor of metalloproteinase-3 (TIMP-3). Correspondingly, secreted levels of TIMP-3 and PAI-2 protein declined in the presence of dysregulated deltaNp63alpha, while secreted maspin protein levels remained stable. Intracellular maspin protein expression decreased in response to overexpressed deltaNp63alpha, as did intracellular PAI-2. Unlike PAI-2 and maspin, TIMP-3 protein was not detected intracellularly in control or deltaNp63alpha-overexpressing keratinocytes, supporting a solely extracellular function for TIMP-3. Electrophoretic mobility shift assays using a p53/p63 consensus DNA binding sequence from the maspin promoter revealed binding of an endogenous transcription factor(s) to the consensus sequence in normal keratinocytes that was disrupted by overexpressed deltaNp63alpha. This binding was also interrupted by the addition of a p73 antibody, but not antibodies to p63 or p53, and was absent in samples derived from p73(-/-) keratinocytes, confirming p73 as a constituent of the endogenous transcription factor complex. These data suggest protease inhibitors as novel targets of dysregulated deltaNp63alpha in cancer pathogenesis.
2013-02-26 | GSE34862 | GEO
Project description:The p53 homologue, p63, is critical for normal epidermal development. While overexpression of deltaNp63alpha has been reported in squamous cell cancers, the contribution of p63 to cancer pathogenesis remains unclear. We previously demonstrated that overexpressed deltaNp63alpha aberrantly maintains proliferation of primary epidermal keratinocytes under conditions that normally induce growth arrest and differentiation. To identify target genes impacted by dysregulated deltaNp63alpha that may contribute to squamous cancer development and progression, microarray analyses were performed. Herein we report that elevated deltaNp63alpha differentially regulates genes in primary mouse keratinocytes involved in a variety of cellular functions, including cell cycle regulation, differentiation, skin barrier formation and function, apoptosis, host defense/inflammation, adhesion, migration and invasion. Of note, multiple protease inhibitor mRNAs were coordinately downregulated under both proliferating and differentiating culture conditions. These downregulated genes include two serine protease inhibitors: maspin (serpinB5) and plasminogen activator inhibitor-2 (PAI-2; serpinB2), as well as a tissue inhibitor of metalloproteinase-3 (TIMP-3). Correspondingly, secreted levels of TIMP-3 and PAI-2 protein declined in the presence of dysregulated deltaNp63alpha, while secreted maspin protein levels remained stable. Intracellular maspin protein expression decreased in response to overexpressed deltaNp63alpha, as did intracellular PAI-2. Unlike PAI-2 and maspin, TIMP-3 protein was not detected intracellularly in control or deltaNp63alpha-overexpressing keratinocytes, supporting a solely extracellular function for TIMP-3. Electrophoretic mobility shift assays using a p53/p63 consensus DNA binding sequence from the maspin promoter revealed binding of an endogenous transcription factor(s) to the consensus sequence in normal keratinocytes that was disrupted by overexpressed deltaNp63alpha. This binding was also interrupted by the addition of a p73 antibody, but not antibodies to p63 or p53, and was absent in samples derived from p73(-/-) keratinocytes, confirming p73 as a constituent of the endogenous transcription factor complex. These data suggest protease inhibitors as novel targets of dysregulated deltaNp63alpha in cancer pathogenesis. Keratinocytes were transduced with adenoviruses encoding deltaNp63alpha. Keratinocytes were either maintained in low calcium conditions (0.05 mM for 24 hours) (n=6) or high calcium conditions (0.12 mM for 24 hours) (n=6). Control samples consisted of keratinocytes transduced with adenoviruses encoding beta-galactosidase also treated with low calcium (n=6) and high calcium (n=6) conditions. Twelve technical repeat microarray experiments were conducted, pairing high-calcium deltaNp63alpha samples with high-calcium beta-galactosidase samples (n=6) and low-calcium deltaNp63alpha samples with low-calcium beta-galactosidase samples (n=6). Six of the technical repeats were conducted as reverse-fluoro experiments.
2013-02-26 | E-GEOD-34862 | biostudies-arrayexpress
Project description:sh RNA of p73 in Fibroblasts compared to non-silencing control Keywords: cell growth, shRNA, p73
2008-04-01 | GSE7201 | GEO
Project description:Rationale: Multiciliated cell (MCC) loss/dysfunction is common in the small airways of patients with COPD but it is unclear if this contributes to COPD lung pathology. Objectives: To determine whether loss of MCCs causes a COPD-like phenotype in mice and explore a potential role for the transcription factor p73 in COPD. Methods: p73floxE7-E9 mice were crossed with Shh-Cre mice to generate mice lacking MCCs in the airway epithelium. The resulting p73airway mice were analyzed using electron microscopy, flow cytometry, morphometry, forced oscillation technique, and single-cell RNA sequencing. Further, the effects of cigarette smoke on p73 transcript and protein expression were examined using in vitro and in vivo models and in studies including airway epithelium from smokers and COPD patients. Measurements and Main Results: Loss of functional p73 in the respiratory epithelium resulted in a near-complete absence of MCCs in p73airway mice. In adulthood, these mice spontaneously developed neutrophilic inflammation and emphysema-like lung remodeling and had progressive loss of secretory cells. Exposure of normal airway epithelium cells to cigarette smoke rapidly and durably suppressed p73 expression in vitro and in vivo. Further, TP73 mRNA expression was reduced in the airways of current smokers (n=82) compared to former smokers (n=69) and p73-expressing MCCs were reduced in the small airways of COPD patients (n=11) compared non-COPD controls (n=12). Conclusions: Loss of functional p73 in murine airway epithelium results in the absence of MCCs and promotes COPD-like lung pathology. In smokers and patients with COPD, loss of p73 may contribute to MCC loss or dysfunction.
2023-11-20 | GSE240096 | GEO
Project description:The integral role of p53 in tumor suppression has promted many laboratories to perform extensive analyses of signaling pathways downstream of the p53 family of sequence-specific DNA binding transcription factors (p53 and its homologs p63 and p73). Despite the ability of p73 to regulate many p53 family target genes, little is known about the specific pathways that modulate p73 during development, tumorigenesis and tumor therapy. In this study we present a gene signature-based approach for connecting signaling pathways to transcription factors, as exemplified by p73. We generated a p73 gene signature by integrating whole-genome chromatin immunoprecipitation and expression profiling. Keywords: Transcription factor analysis
2008-08-06 | GSE11672 | GEO
Project description:The integral role of p53 in tumor suppression has promted many laboratories to perform extensive analyses of signaling pathways downstream of the p53 family of sequence-specific DNA binding transcription factors (p53 and its homologs p63 and p73). Despite the ability of p73 to regulate many p53 family target genes, little is known about the specific pathways that modulate p73 during development, tumorigenesis and tumor therapy. In this study we present a gene signature-based approach for connecting signaling pathways to transcription factors, as exemplified by p73. We generated a p73 gene signature by integrating whole-genome chromatin immunoprecipitation and expression profiling. Experiment Overall Design: H1299 lung carcinoma cells were infected with p73 expressing or control adenovirus for 5 h and then harvested.
2008-10-20 | E-GEOD-11626 | biostudies-arrayexpress