Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA383400 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5456580.fastq.gz | Fastqsanger.gz | |||
| SRR5456581.fastq.gz | Fastqsanger.gz | |||
| SRR5456582.fastq.gz | Fastqsanger.gz | |||
| SRR5456583.fastq.gz | Fastqsanger.gz | |||
| SRR5456584.fastq.gz | Fastqsanger.gz |
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Project description:The RAC1 GTPase and its effector PAK1 have been found to be overexpressed or hyperactivated in colorectal cancer (CRC), one of the most prevalent types of cancer in the world. This overexpression frequently correlates with chemoresistance and less favourable prognoses. We previously showed that the activation of RAC1/PAK1 signalling promotes a switch between the BCL6 transcriptional repressor and the STAT5 transcriptional activator at a subset of pro-proliferative gene promoters. Here we used ChIP-Seq, under conditions of pathway inhibition and stimulation, to identify the BCL6/STAT5-switch binding sites throughout the genome. Using a knowledge-driven pipeline for ChIP-Seq data analysis, we identify 3774 genomic features associated to the switch-motif, with a significant enrichment in protein-coding genes involved in DNA damage repair pathways. Stimulation of RAC1/PAK1 signalling in DLD-1 CRC cells increased the expression of these genes and significantly enhanced DNA repair in response to damage induced by alkylating agents. Our results reveal a new transcriptional reprogramming mechanism whereby the alternate binding of a repressor and an activator protein to low-affinity motifs is used to coordinate a transcriptional response to DNA damage. This mechanism may link the upregulation of the RAC1/PAK1 pathway to the chemoresistant phenotype of aggressive CRCs.
2019-04-30 | GSE97938 | GEO
Project description:High levels of placental growth factor (PlGF) are pathological, however its function in endometrial cells remains to be investigated. Cell proliferation and motility requires actin reorganization, which is under the control of various signalling pathways including Rac1 and PAK1 proteins. In this study, we explored whether PlGF induces change in endometrial mechanics by modifying actin cytoskeleton thus contributing to cell stiffness at the maternal interface. To this end, human endometrial stromal cells (EnSCs) were treated with 20 ng/mL for 6 days with PlGF and its influence on cellular mechanics was investigated with atomic force microscopy (AFM), electrical impedance spectroscopy and proteomics methods. Proteomic analysis shows PlGF upregulated RhoGTPases activating proteins and extracellular matrix organization associated proteins. Rac1 and PAK1 transcript levels, activity and actin polymerization were significantly increased with in vitro PlGF treatment. AFM further revealed an increase in cell stiffness with PlGF. The PlGF effect on actin polymerization was inhibited with siRNA- Rac1, PAK1 and WAVE2. PlGF induced cell stiffness was pharmacologically reversed with pravastatin, resulting in improved trophoblast cell invasion as measured using electrical impedance spectroscopy. Thus, PlGF treatment leads to enhanced Rac1 and PAK1 levels, leading to an increase in cell stiffness, impairing trophoblast invasion. Taken together, aberrant PlGF levels can contribute to an altered pre-pregnancy maternal microenvironment and offers a coherent and unifying explanation for the pathological changes observed in pre-eclampsia (PE) conditions.
2024-06-23 | PXD050237 | Pride
Project description:Rac1, a member of the small G protein Rho family, has been implicated in neurodegenerative diseases. However, its role in axon degeneration is not fully understood. Here we found that activation of Rac1 exacerbated axonal transport damage in an experimental glaucoma model. Inhibiting Rac1 activity by genetic or pharmacological methods alleviated the dysfunction of axonal transport and improved the integrity of microtubule by upregulating the expression of β-III tubulin and myelin basic protein. Rac1 interacted with Sirt1, a key molecule of Wallerian degeneration, which regulated the activity of PAK1, a downstream molecule of Rac1. Furthermore, Rac1 modulated Kif motors at the transcriptional level, among which Kif2a, a lysosome-location regulator, was negatively regulated by Rac1. Intravitreal injection of Kif2a siRNA reversed the improvement of Rac1 inhibition-mediated axonal transport through reducing autophagolysosomes. Our results suggest that Rac1/Kif2a accelerates the process of RGC axon degeneration by impairing the autophagic flux in glaucoma, which may be an intriguing therapy target for glaucoma.
2024-12-01 | GSE247696 | GEO
Project description:Aims/ hypothesis: p21 (Cdc42/Rac1) activated Kinase 1 (PAK1) is depleted in type 2 diabetic human islets compared to non-diabetic (ND) human islets, and acute PAK1 restoration to type 2 diabetic human islets can restore insulin secretory function ex vivo. We hypothesized that beta cell specific PAK1 enrichment in vivo carries the capacity to mitigate high-fat diet-induced glucose intolerance by increasing the functional beta cell mass. Methods: Type 2 diabetic or ND human islets expressing exogenous PAK1 specifically in beta cells were used for bulk RNA-sequencing (RNA-seq). Human EndoC-
2024-09-25 | GSE239381 | GEO
Project description:Aims/ hypothesis: p21 (Cdc42/Rac1) activated Kinase 1 (PAK1) is depleted in type 2 diabetic human islets compared to non-diabetic (ND) human islets, and acute PAK1 restoration to type 2 diabetic human islets can restore insulin secretory function ex vivo. We hypothesized that beta cell specific PAK1 enrichment in vivo carries the capacity to mitigate high-fat diet-induced glucose intolerance by increasing the functional beta cell mass. Methods: Type 2 diabetic or ND human islets expressing exogenous PAK1 specifically in beta cells were used for bulk RNA-sequencing (RNA-seq). Human EndoC-
2024-09-25 | GSE239306 | GEO
Project description:In the central nervous system (CNS), myelin formation by oligodendrocytes (OLs) relies on actin dynamics. Actin polymerization supports the ensheathment step, when the OL process contacts and surrounds a selected portion of axon. While a drastic shift to actin depolymerization is then required to enable the wrapping process and the formation of a multilayered myelin sheath. Molecular mechanisms regulating this switch to actin depolymerization are not fully elucidated. P21-activated kinase 1 (PAK1), a downstream effector of Rho GTPases Rac1 and Cdc42, highly expressed in OLs, can regulate actin dynamics through its kinase activity. We found that PAK1 loss-of-function in OLs, in vivo, stimulates the wrapping and the thickening of myelin sheaths. We showed that PAK1 is highly expressed in myelinating OLs, yet in its inactive form, the one with the ability to trigger actin disassembly. Interestingly, we found that modulations of PAK1 kinase activity control actin dynamics in OLs, thereby myelin formation. Our data demonstrate that PAK1 inactivation in OLs is required for actin depolymerization and proper myelin formation, suggesting the presence of an endogenous PAK1 inhibitor in myelinating OLs. Proteomic analysis of PAK1 binding partners enabled us to identify several proteins likely to regulate its activity.
2024-06-03 | PXD044344 | Pride
Project description:Interleukin 9 (IL-9) is a γc-family cytokine that is highly produced by T-helper 9 (Th9) cells and regulates a range of immune responses, including allergic inflammation. Here we show that IL-2–JAK3–STAT5 signaling is required for Th9 differentiation, with critical STAT5 binding sites in the Il9 (the gene encoding IL-9) promoter. IL-2 also inhibited B cell lymphoma 6 (BCL6) expression, and over- expression of BCL6 impaired Th9 differentiation. In contrast to IL-2, IL-21 induced BCL6 and diminished IL-9 expression in wild-type but not Bcl6−/− cells, whereas Th9 differentiation was increased in Il21−/− or Il21r−/− T cells. Interestingly, BCL6 bound in proximity to many STAT5 and STAT6 binding sites, including at the Il9 promoter. Moreover, there was increased BCL6 and decreased STAT binding at this site in cells treated with blocking antibodies to IL-2 and the IL-2 receptor, suggesting a possible BCL6–STAT5 binding competition that influences IL-9 production. BCL6 binding was also increased when cells were Th9-differentiated in the presence of IL-21. Thus, our data reveal not only direct IL-2 effects via STAT5 at the Il9 gene, but also opposing actions of IL-2 and IL-21 on BCL6 expression, with increased BCL6 expression inhibiting IL-9 production. These data suggest a model in which increasing BCL6 expression decreases efficient Th9 differentiation, indicating possible distinctive approaches for controlling this process. Genome-wide transcription factors mapping and binding of STAT5B and STAT6 in mouse polarized Th9 cells treated with or without blocking antibodies to IL-2 (anti-IL-2). RNA-Seq is conducted in WT and Il2-/- mice.
2014-02-20 | E-GEOD-41317 | biostudies-arrayexpress
Project description:Sex-dependent pituitary growth hormone (GH) secretory patterns determine the sex-biased expression of >1,000 genes in mouse and rat liver, affecting lipid and drug metabolism, inflammation and disease. A fundamental biological question is how robust differential expression can be achieved for hundreds of sex-biased genes simply based on the GH input signal pattern: pulsatile GH stimulation in males vs. near-continuous GH exposure in females. STAT5 is an essential transcriptional mediator of the sex-dependent effects of GH in the liver, but the mechanisms that underlie its sex-dependent actions are obscure. Here we elucidate the dynamic, sex-dependent binding of STAT5 and the GH/STAT5-regulated repressor BCL6 to mouse liver chromatin, revealing the counteractive interplay between these two regulators of liver sex-specificity. Our findings establish a close correlation between sex-dependent STAT5 binding and sex-biased target gene expression. Moreover, sex-dependent STAT5 binding correlated positively with sex-biased DNase hypersensitivity and H3-K4me1 and H3-K4me3 (activating) marks, correlated negatively with sex-biased H3-K27me3 (repressive) marks, and was associated with sex-differentially enriched motifs for HNF6/CDP factors. Importantly, BCL6 binding was preferentially associated with repression of female-biased STAT5 targets in male liver. Furthermore, BCL6 and STAT5 common targets but not BCL6 unique targets showed strong enrichment for lipid and drug metabolism. These findings provide a comprehensive, genome-wide view of the mechanisms whereby these two GH-regulated transcription factors establish and maintain sex differences affecting liver physiology and disease. The approaches used here to characterize sex-dependent STAT5 and BCL6 binding can be applied to other condition-specific regulatory factors and binding sites and their interplay with co-operative chromatin-binding factors. Mouse livers were excised from individual male and female mice killed at either a peak of STAT5 binding activity, or during the growth hormone (GH) interpulse interval, when STAT5 activity is either low (females) or essentially undetectable (males). Sonicated, cross-linked liver nuclear chromatin was then used to identify STAT5 binding sites by ChIP-Seq.
2011-12-18 | E-GEOD-31578 | biostudies-arrayexpress
Project description:Interleukin 9 (IL-9) is a γc-family cytokine that is highly produced by T-helper 9 (Th9) cells and regulates a range of immune responses, including allergic inflammation. Here we show that IL-2–JAK3–STAT5 signaling is required for Th9 differentiation, with critical STAT5 binding sites in the Il9 (the gene encoding IL-9) promoter. IL-2 also inhibited B cell lymphoma 6 (BCL6) expression, and over- expression of BCL6 impaired Th9 differentiation. In contrast to IL-2, IL-21 induced BCL6 and diminished IL-9 expression in wild-type but not Bcl6−/− cells, whereas Th9 differentiation was increased in Il21−/− or Il21r−/− T cells. Interestingly, BCL6 bound in proximity to many STAT5 and STAT6 binding sites, including at the Il9 promoter. Moreover, there was increased BCL6 and decreased STAT binding at this site in cells treated with blocking antibodies to IL-2 and the IL-2 receptor, suggesting a possible BCL6–STAT5 binding competition that influences IL-9 production. BCL6 binding was also increased when cells were Th9-differentiated in the presence of IL-21. Thus, our data reveal not only direct IL-2 effects via STAT5 at the Il9 gene, but also opposing actions of IL-2 and IL-21 on BCL6 expression, with increased BCL6 expression inhibiting IL-9 production. These data suggest a model in which increasing BCL6 expression decreases efficient Th9 differentiation, indicating possible distinctive approaches for controlling this process.
2014-02-20 | GSE41317 | GEO
Project description:Personalized treatment of complex diseases is an unmet medical need pushing towards drug biomarker identification of one drug-disease combination at a time. Here, we used a novel computational approach for modeling cell-centered individual-level network dynamics from high-dimensional blood data to predict infliximab response and uncover individual variation of non-response. We identified and validated that the RAC1-PAK1 axis is predictive of infliximab response in inflammatory bowel disease. Intermediate monocytes, which closely correlated with inflammation state, play a key role in the RAC1-PAK1 responses, supporting their modulation as a therapeutic target. This axis also predicts response in Rheumatoid arthritis, validated in three public cohorts. Our findings support pan-disease drug response diagnostics from blood, implicating common mechanisms of drug response or failure across diseases.
2024-11-01 | GSE186963 | GEO