JNK activation dynamics drive distinct gene expression patterns over time mediated by mRNA stability
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ABSTRACT:
PROVIDER: PRJNA1267122 | ENA |
REPOSITORIES: ENA
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Project description:c-Jun N-terminal kinase (JNK) plays a major role in the regulation of cell death. Numerous studies have highlighted how the dynamics of this kinase dictate whether cells survive in response to cellular stress or induce cell death mechanisms. However, it is less clear how these dynamics potentially contribute to downstream gene expression patterns through regulated transcription factors like c-Jun. To investigate this question, we used a treatment strategy with the JNK agonist anisomycin to drive specific dynamics; sustained, transient, or pulsed activation, and assessed the impact on downstream gene expression patterns. We observed that multiple gene expression patterns emerged depending on the dynamics of JNK activation. Ordinary Differential Equation (ODE) models suggest that a subset of these clusters are mediated by mRNA stability and supported by measured mRNA decay rates. Specific gene clusters also show enrichment in specific cellular pathways, including cell death and inflammatory signaling, suggesting these dynamics contribute to differential regulation of these pathways. These findings highlight another contribution of JNK dynamics to the regulation of cellular responses to stress stimuli.
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Project description:In inflamed tissue, normal signal transduction pathways are altered by extracellular signals. For example, the JNK pathway is activated in psoriatic skin, which makes it an attractive target for treatment. To define comprehensively the JNK-regulated genes in human epidermal keratinocytes, we compared the transcriptional profiles of control and JNK inhibitor-treated keratinocytes, using DNA microarrays. We identified the differentially expressed genes 1, 4, 24, and 48 h after the treatment with SP600125. Surprisingly, the inhibition of JNK in keratinocyte cultures in vitro induces virtually all aspects of epidermal differentiation in vivo: transcription of cornification markers, inhibition of motility, withdrawal from the cell cycle, stratification, and even production of cornified envelopes. The inhibition of JNK also induces the production of enzymes of lipid and steroid metabolism, proteins of the diacylglycerol and inositol phosphate pathways, mitochondrial proteins, histones, and DNA repair enzymes, which have not been associated with differentiation previously. Simultaneously, basal cell markers, including integrins, hemidesmosome and extracellular matrix components, are suppressed. Promoter analysis of regulated genes finds that the binding sites for the forkhead family of transcription factors are over-represented in the SP600125-induced genes and c-Fos sites in the suppressed genes. The JNK-induced proliferation appears to be secondary to inhibition of differentiation. The results indicate that the inhibition of JNK in epidermal keratinocytes is sufficient to initiate their differentiation program and suggest that augmenting JNK activity could be used to delay cornification and enhance wound healing, whereas attenuating it could be a differentiation therapy-based approach for treating psoriasis.
2007-10-26 | E-GEOD-4828 | biostudies-arrayexpress
Project description:Oxidative stress-dependent genes are defined as those induced or suppressed by H2O2 treatement in rat vascular smooth muscle cells. JNK-induced genes in rat vascular smooth muscle cells are defined as those induced by adenoviruses encoding constitutively active MKK7 (caMKK7) + wild type JNK1 (wtJNK1) and suppressed by adenovirus encoding dominant negative JNK1 (APF). JNK-suppressed genes in rat vascular smooth muscle cells are defined as those suppressed by adenoviruses encoding constitutively active MKK7 (caMKK7) + wild type JNK1 (wtJNK1) and induced by adenovirus encoding dominant negative JNK1 (APF). Adenovirus encoding nuclear localizing GFP was used as a control. Keywords = vascular smooth muscle Keywords = hydrogen peroxide Keywords = c-Jun N-terminal kinase Keywords = JNK Keywords = adenovirus Keywords = oxidative stress Keywords: repeat sample
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Project description:RNAseq analysis of gene expression in Liver of Control and JNK deficient mice fed a control or a High fat diet Contro(Albcre+)l and mice with liver-specific defiency of JNK (Alb Cre+ Jnk1flox/flox, Jnk2flox/flox or Jnk1flox/floxJnk2flox/flox) were fed a control or a high fat diet for 16 weeks. Gene expression analysis in liver was analyzed by RNAseq
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Project description:Members of the JNK pathway have been found to be mutated in human breast cancer. Mouse studies examining JNK loss in different tissues have demonstrated that the JNK pathway can play a role in cancer. Using and autochthonous mouse model, we found that JNK deficiency on a p53-null background resulted in more rapid tumor onset. To learn more about these tumors we generated cells lines and performed various in vitro assays, as well as RNAseq in hope of finding differentially expressed genes that may explain the differences we observed in vivo.
2018-05-29 | GSE92560 | GEO
Project description:Signaling mediates cellular responses to extracellular stimuli. The c-Jun NH2-terminal kinase (JNK) pathway exemplifies one sub-group of Mitogen-activated protein (MAP) kinases, which besides established functions in stress response, also contributes to developmental processes by an unknown mechanism 1-4. Here we show by genome-wide location analysis that JNK binds directly to a large set of active promoters during differentiation of stem cells to neurons. Bound promoters are not enriched for the canonical AP?1 target sites yet for binding motifs for the transcription factor NF?Y. NF-Y indeed occupies these predicted sites genome-wide in vivo and overexpression of a dominant-negative form of NF?YA reduces JNK presence on chromatin. Histone H3 is a substrate for JNK kinase activity in vitro and JNK bound promoters are preferentially enriched for Histone H3 phosphorylated at Serine 10. Inhibition of JNK signaling in postmitotic neurons reduces this chromatin phosphorylation as well as expression of target genes. Together this establishes MAP kinase binding and function on chromatin at a novel class of target genes during stem cell differentiation. Our Dataset comprises 5 ChIP-seq samples using chromatin from ES, NP and TN cells which was immunoprecipitated, using antibodies against H3K27me3, H3K4me2, RNA Pol II, JNK1/3 and NF-YA. From the same cells we generated biological replicates of RNA-seq data.
2011-12-18 | E-GEOD-25532 | biostudies-arrayexpress
Project description:We found that transient inhibition of JNK pathway increased short term-HSC frequency in cord blood CD34+ cells by 12.56 folds. Transcriptome analysis shows that inhibition of JNK pathway upregulated HSC-specific and anti-oxidative gene expression, prevented upregulation of cell cycle entry, oxidative phosphorylation and glycolysis related gene expression, and downregulated reactive oxygen species (ROS) active gene expression. Consistently, cell cycle and metabolic analysis show that inhibition of JNK pathway prevented HSC from cell cycle entry, glucose uptake increase and ROS accumulation. Accordingly, transient inhibition of JNK pathway also enhanced long term-HSC recovery during cord blood CD34+ cell collection. Collectively, these findings suggest that transient inhibition of JNK pathway could promote quiescent state of HSCs by preventing cell cycle entry and metabolic activation, thus improving HSC recovery and engraftment ability.
2022-06-29 | GSE165501 | GEO
Project description:Signaling mediates cellular responses to extracellular stimuli. The c-Jun NH2-terminal kinase (JNK) pathway exemplifies one sub-group of Mitogen-activated protein (MAP) kinases, which besides established functions in stress response, also contributes to developmental processes by an unknown mechanism 1-4. Here we show by genome-wide location analysis that JNK binds directly to a large set of active promoters during differentiation of stem cells to neurons. Bound promoters are not enriched for the canonical AP?1 target sites yet for binding motifs for the transcription factor NF?Y. NF-Y indeed occupies these predicted sites genome-wide in vivo and overexpression of a dominant-negative form of NF?YA reduces JNK presence on chromatin. Histone H3 is a substrate for JNK kinase activity in vitro and JNK bound promoters are preferentially enriched for Histone H3 phosphorylated at Serine 10. Inhibition of JNK signaling in postmitotic neurons reduces this chromatin phosphorylation as well as expression of target genes. Together this establishes MAP kinase binding and function on chromatin at a novel class of target genes during stem cell differentiation.
2011-12-18 | GSE25532 | GEO
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