Tubular Foxp2 promotes kidney fibrosis by regulating epithelial-mesenchymal transition and cell cycle arrest
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1041761 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26861605_1.fastq.gz | Fastqsanger.gz | |||
| SRR26861605_2.fastq.gz | Fastqsanger.gz | |||
| SRR26861606_1.fastq.gz | Fastqsanger.gz | |||
| SRR26861606_2.fastq.gz | Fastqsanger.gz |
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Project description:Kidney fibrosis results in progressive loss of function, ultimately leading to kidney failure, for which there are limited effective therapeutic strategies. The transcription factor, Forkhead box P2 (Foxp2), has been implicated in organ development and tumorigenesis through its association with the epithelial-to-mesenchymal transition (EMT) process. In this study, we uncovered a novel role of Foxp2 in kidney fibrosis. Expression of Foxp2 was upregulated in kidney tubules from both human chronic glomerulonephritides and animal models of chronic kidney disease. In vitro, Foxp2 was induced in tubular epithelial cells via TGF-β/Smad3 signaling while knockdown of Foxp2 suppressed TGF-β-induced EMT and accumulation of extracellular matrix proteins. In vivo, tubule-specific deletion of Foxp2 attenuated kidney inflammation and tubulointerstitial fibrosis in murine unilateral ureteral obstruction and unilateral ischemic-reperfusion models of progressive CKD, which were accompanied by reduction in cell cycle arrest. Mechanistically, overexpression of Foxp2 inhibited tubular cell proliferation with induction of G2/M cell cycle arrest. Using chromatin-immunoprecipitation sequencing, we identified Foxp2 target genes that are enriched in PI3K/Akt and TGF-β signaling pathways, and further revealed that Foxp2 directly regulated the transcriptional activities of collagen-1, E-cadherin and p21 that are involved in EMT and cell cycle arrest, thereby promoting the profibrotic process. Collectively, our findings provide novel evidence that Foxp2 regulates TGF-β-induced EMT and cell cycle arrest, the key signaling pathways of kidney fibrosis, and suggest that Foxp2 may be a potential therapeutic target for kidney fibrosis.
2024-12-10 | GSE248092 | GEO
Project description:To study the underlying mechanism of tumor initation driven by FOXP2, we performed transcriptome analysis of transformed NIH3T3 overexpressing FOXP2 or FOXP2-CEPD1 and control cells to explore the FOXP2-related transcriptome in tumorigenesis.
2019-05-08 | GSE114350 | GEO
Project description:It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene.of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting an effect of the humanized Foxp2 allele on basal ganglia. In the striatum, a part of the basal ganglia that is affected in humans with a speech deficit due to one non-functional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one non-functional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans. In this particular experiment, we investigate the effects of human Foxp2 (Foxp2hum) and the non-functional Foxp2 allele on striatal gene expression in embryonic, young and adult mice. We determined genome-wide gene expression patterns in striatal biopsies from Foxp2hum/hum, Foxp2wt/ko and Foxp2wt/wt mice using high-density oligonucleotide arrays. The animals were derived from two independent FoxP2 knock-in strains and one knock-out strain. In total 71 animals were used, 29 males and 42 females. The mice ages were E16.5, P15, P18, P21 and P95 when sacrificed. The microarrays were processed in totally six batches.
2010-05-22 | E-GEOD-13588 | biostudies-arrayexpress
Project description:It has been proposed that two amino acid substitutions in the transcription factor FOXP2 have been positively selected during human evolution due to effects on aspects of speech and language. Here, we introduce these substitutions into the endogenous Foxp2 gene.of mice. Although these mice are generally healthy, they have qualitatively different ultrasonic vocalizations, decreased exploratory behavior and decreased dopamine concentrations in the brain suggesting an effect of the humanized Foxp2 allele on basal ganglia. In the striatum, a part of the basal ganglia that is affected in humans with a speech deficit due to one non-functional FOXP2 allele, we find that medium spiny neurons have increased dendrite lengths and increased synaptic plasticity. Since mice carrying one non-functional Foxp2 allele show opposite effects, this suggests that alterations in cortico-basal ganglia circuits might have been important for the evolution of speech and language in humans. In this particular experiment, we investigate the effects of human Foxp2 (Foxp2hum) and the non-functional Foxp2 allele on striatal gene expression in embryonic, young and adult mice.
2009-03-02 | GSE13588 | GEO
Project description:In humans, mutations in the transcription factor encoding gene, FOXP2, are associated with language and Autism Spectrum (ASD) Disorders, the latter characterized by deficits in social interactions. However, little is known regarding the function of Foxp2 in male or female social behavior. Our previous studies in mice revealed high expression of Foxp2 within the medial subnucleus of the amygdala (MeA), a limbic brain region highly implicated in innate social behaviors such as mating, aggression, and parental care. Here, using a comprehensive panel of behavioral tests in male and female Foxp2+/- heterozygous mice, we investigated the role Foxp2 plays in MeA-linked innate social behaviors. We reveal significant deficits in olfactory processing, social interaction, mating, aggressive and parental behaviors. Interestingly, some of these deficits displayed in a sex-specific manner. To examine the consequences of Foxp2 loss of function specifically in the MeA, we conducted a proteomic analysis of microdissected MeA tissue and found sex differences in a host of proteins implicated in neuronal communication, connectivity and dopamine signaling. Consistent with this, we discovered that MeA Foxp2-lineage cells were responsive to dopamine with differences between males and females. Thus, our findings reveal a central and sex-specific role for Foxp2 in social behavior and MeA function.
2021-07-07 | PXD026978 | Pride
Project description:Alterations to corticostriatal glutamatergic function are early pathophysiological changes associated with Huntington?s disease (HD). The factors that regulate the maintenance of corticostriatal glutamatergic synapses post-developmentally are not well understood. Recently, the striatum-enriched transcription factor Foxp2 was implicated in the development of these synapses. Here we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type mice leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant Huntingtin protein (mHTT). Foxp2 overexpression in HD model mice leads to altered expression of several genes associated with synaptic function, genes which present new targets for normalization of corticostriatal dysfunction in HD.
2017-12-05 | GSE104990 | GEO
Project description:We observed different gene expression by overexpressing the transcription factor FOXP2 in U2OS cells compared to mock-transfected cells. Additionally, we found β-catenin as co-activator binding directly to FOXP2. Activation of Wnt signaling was changing the transcriptional activity of FOXP2. Other functional and regulatory elements were found within FOXP2 and were confirmed by RNA-Seq.
2020-06-01 | GSE138938 | GEO
Project description:The transcription repressor FOXP2 is a crucial player in nervous system evolution and development of humans and songbirds. In spite of its relevance, the FOXP2-controlled network and its functional implications are only partially understood. Therefore, we analyzed the transcriptomes of human neuroblastoma cells (SH-SY5Y) stably overexpressing human, chimpanzee, macaque, and marmoset FOXP2 cDNAs. Clones carrying empty vector served as a standard of baseline expression. All conditions were represented by two biological replicates (A, B), each. By comparing expression levels (bases which map per kb of exon model per million mapped bases) across the different conditions we were able to identify genes with differential expression in clones overexpressing human FOXP2 relative to each other condition.
2017-08-31 | GSE100291 | GEO
Project description:Mutations in FOXP2, a member of the forkhead family of transcription factors, are the only known cause of developmental speech and language disorders in humans. To date, there are no known targets of human FOXP2 in the nervous system. The identification of FOXP2 targets in the developing human brain therefore provides a unique tool with which to explore the development of human language and speech. Here we define FOXP2 targets in human basal ganglia (BG) and inferior frontal cortex (IFC) utilizing chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) and validate the functional regulation of targets in vitro. ChIP-chip identified 285 FOXP2 targets in fetal human brain; significant overlap of targets in BG and IFC, indicate a core set of 34 transcriptional targets of FOXP2. We identified targets specific to the IFC or BG, not observed in lung, suggesting important regional and tissue differences in FOXP2 activity. Many target genes are known to play critical roles in specific aspects of CNS patterning or development, such as neurite outgrowth, as well as plasticity. Subsets of the FOXP2 transcriptional targets are either under positive selection in humans, or differentially expressed between human and chimpanzee brain. This is the first ChIP-chip study using human brain tissue, making the FOXP2 target genes identified in these studies important to understanding the pathways regulating speech and language in the developing human brain. These data provide the first insight into the functional network of genes directly regulated by FOXP2 in human brain and by evolutionary comparisons, highlight genes likely to be involved in the development of human higher order cognitive processes. Keywords: ChIP-chip
2007-12-31 | GSE8547 | GEO
Project description:Renal fibrosis is a common underlying process of progressive kidney diseases. We investigated the role of macrophage migration inhibitory factor (MIF), a pleiotropic proinflammatory cytokine, in this process. In mice subjected to unilateral ureteral obstruction, genetic deletion or pharmacologic inhibition of MIF aggravated fibrosis and inflammation, whereas treatment with recombinant MIF was beneficial, even in established fibrosis. In two other models of progressive kidney disease, global Mif deletion or MIF inhibition also worsened fibrosis and inflammation and associated with worse kidney function. Renal MIF expression was reduced in tubular cells in fibrotic compared with healthy murine and human kidneys. Bone marrow chimeras showed that Mif expression in bone marrow-derived cells did not affect fibrosis and inflammation after UUO. However, Mif gene deletion restricted to renal tubular epithelial cells aggravated these effects. In LPS-stimulated tubular cell cultures, Mif deletion led to enhanced G2/M cell-cycle arrest and increased expression of the CDK inhibitor 1B (p27Kip1) and of proinflammatory and profibrotic mediators. Furthermore, MIF inhibition reduced tubular cell proliferation in vitro In all three in vivo models, global Mif deletion or MIF inhibition caused similar effects and attenuated the expression of cyclin B1 in tubular cells. Mif deletion also resulted in reduced tubular cell apoptosis after UUO. Recombinant MIF exerted opposing effects on tubular cells in vitro and in vivo Our data identify renal tubular MIF as an endogenous renoprotective factor in progressive kidney diseases, raising the possibility of pharmacologic intervention with MIF pathway agonists, which are in advanced preclinical development.
| S-EPMC5698074 | biostudies-literature