Similar Datasets
Project description:Current models posit that nuclear speckles (NSs) serve as reservoirs of splicing factors and facilitate post-transcriptional processing of mRNA. Here, we discovered that ribotoxic stress leads to a profound reorganization of NSs with enhanced recruitment of factors required for 5' and 3' splice site recognition including the RNA-binding protein TIAR, U1 snRNP proteins and U2-associated factor 65, as well as serine 2 phosphorylated RNA polymerase II. NS reorganization is dependent on the stress-activated p38 mitogen activated protein kinase (MAPK), and goes along with splicing activation of both pre-existing and nascent pre-mRNAs. In particular, ribotoxic stress causes targeted excision of retained introns from pre-mRNAs of immediate early genes (IEGs), whose transcription is induced during the stress response. Importantly, enhanced splicing of the IEGs ZFP36 and FOS is accompanied by re-localization of the corresponding mRNAs to NSs. Our study reveals NSs as a dynamic compartment that is remodeled under stress conditions to promote the excision of retained introns and thereby enhance the expression and processing of IEG mRNAs.
2021-08-06 | GSE181446 | GEO
Project description:Current models posit that nuclear speckles (NSs) serve as reservoirs of splicing factors and facilitate post-transcriptional processing of mRNA. Here, we discovered that ribotoxic stress leads to a profound reorganization of NSs with enhanced recruitment of factors required for 5' and 3' splice site recognition including the RNA-binding protein TIAR, U1 snRNP proteins and U2-associated factor 65, as well as serine 2 phosphorylated RNA polymerase II. NS reorganization is dependent on the stress-activated p38 mitogen activated protein kinase (MAPK), and goes along with splicing activation of both pre-existing and nascent pre-mRNAs. In particular, ribotoxic stress causes targeted excision of retained introns from pre-mRNAs of immediate early genes (IEGs), whose transcription is induced during the stress response. Importantly, enhanced splicing of the IEGs ZFP36 and FOS is accompanied by re-localization of the corresponding mRNAs to NSs. Our study reveals NSs as a dynamic compartment that is remodeled under stress conditions to promote the excision of retained introns and thereby enhance the expression and processing of IEG mRNAs.
2023-05-04 | GSE231519 | GEO
Project description:Current models posit that nuclear speckles (NSs) serve as reservoirs of splicing factors and facilitate post-transcriptional processing of mRNA. Here, we discovered that ribotoxic stress leads to a profound reorganization of NSs with enhanced recruitment of factors required for 5' and 3' splice site recognition including the RNA-binding protein TIAR, U1 snRNP proteins and U2-associated factor 65, as well as serine 2 phosphorylated RNA polymerase II. NS reorganization is dependent on the stress-activated p38 mitogen activated protein kinase (MAPK), and goes along with splicing activation of both pre-existing and nascent pre-mRNAs. In particular, ribotoxic stress causes targeted excision of retained introns from pre-mRNAs of immediate early genes (IEGs), whose transcription is induced during the stress response. Importantly, enhanced splicing of the IEGs ZFP36 and FOS is accompanied by re-localization of the corresponding mRNAs to NSs. Our study reveals NSs as a dynamic compartment that is remodeled under stress conditions to promote the excision of retained introns and thereby enhance the expression and processing of IEG mRNAs.
2023-05-04 | GSE231520 | GEO
Project description:Immediate early gene (IEG) expression is coordinated by multiple MAP kinase signaling pathways in a signal specific manner. Stress-activated p38? MAP kinase is implicated in transcriptional regulation of IEGs via MSK-mediated CREB phosphorylation. The protein kinases downstream to p38, MAPKAP kinase (MK) 2 and MK3 have been identified to regulate gene expression at the posttranscriptional levels of mRNA stability and translation. Here, we analyzed stress-induced IEG expression in MK2/3-deficient cells. Ablation of MKs causes a decrease of p38? level and p38-dependent IEG expression. Unexpectedly, restoration of p38? does not rescue the full-range IEG response. Instead, the catalytic activity of MKs is necessary for the major transcriptional activation of IEGs. By transcriptomics, we identified MK2-regulated genes and recognized the serum response element (SRE) as a common promoter element. We show that stress-induced phosphorylation of serum response factor (SRF) at serine residue 103 is significantly reduced and that induction of SRE-dependent reporter activity is impaired and can only be rescued by catalytically active MK2 in MK2/3-deficient cells. Hence, a new function of MKs in transcriptional activation of IEGs via the p38?-MK2/3-SRF-axis is proposed which probably cooperates with MKs' role in posttranscriptional gene expression in inflammation and stress response.
| S-EPMC3074129 | biostudies-literature
Project description:Behavioral changes in response to stressful stimuli can be controlled via adaptive epigenetic changes in neuronal gene expression. Here we indicate a role for the transcriptional corepressor Lysine-Specific Demethylase 1 (LSD1) and its dominant-negative splicing isoform neuroLSD1, in the modulation of emotional behavior. In mouse hippocampus, we show that LSD1 and neuroLSD1 can interact with transcription factor serum response factor (SRF) and set the chromatin state of SRF-targeted genes early growth response 1 (egr1) and c-fos Deletion or reduction of neuro LSD1 in mutant mice translates into decreased levels of activating histone marks at egr1 and c-fos promoters, dampening their psychosocial stress-induced transcription and resulting in low anxiety-like behavior. Administration of suberoylanilide hydroxamine to neuroLSD1(KO)mice reactivates egr1 and c-fos transcription and restores the behavioral phenotype. These findings indicate that LSD1 is a molecular transducer of stressful stimuli as well as a stress-response modifier. Indeed, LSD1 expression itself is increased acutely at both the transcriptional and splicing levels by psychosocial stress, suggesting that LSD1 is involved in the adaptive response to stress.
| S-EPMC4822633 | biostudies-other
Project description:Schlafen 11 (SLFN11) was recently discovered as a cellular restriction factor against replication stress. Here, we show that SLFN11 increases chromatin accessibility genome wide, prominently at active promoters in response to replication stress induced by the checkpoint kinase 1 (CHK1) inhibitor prexasertib or the topoisomerase I (TOP1) inhibitor camptothecin. Concomitantly, SLFN11 selectively activates cellular stress response pathways by inducing the transcription of the immediate early genes (IEGs), including JUN, FOS, EGR1, NFKB2, and ATF3, together with the cell cycle arrest genes CDKN1A (p21WAF1) and GADD45. Both chromatin remodeling and IEG activation require the putative ATPase and helicase activity of SLFN11, whereas canonical extrinsic IEG activation is SLFN11 independent. SLFN11-dependent IEG activation by camptothecin is also observed across 55 non-isogenic NCI-60 cell lines. We conclude that SLFN11 acts as a global regulator of chromatin structure and an intrinsic IEG activator with the potential to engage the innate immune activation in response to replicative stress.
| S-EPMC7240837 | biostudies-literature
Project description:Liquid-liquid phase separation is considered a generic approach to organize membrane-less compartments, enabling the dynamic regulation of phase-separated assemblies to be investigated and pivotal roles of protein posttranslational modifications to be demonstrated. By surveying the subcellular localizations of human deubiquitylases, USP42 was identified to form nuclear punctate structures that are associated with phase separation properties. Bioinformatic analysis demonstrated that the USP42 C-terminal sequence was intrinsically disordered, which was further experimentally confirmed to confer phase separation features. USP42 is distributed to SC35-positive nuclear speckles in a positively charged C-terminal residue- and enzymatic activity-dependent manner. Notably, USP42 directs the integration of the spliceosome component PLRG1 into nuclear speckles, and its depletion interferes with the conformation of SC35 foci. Functionally, USP42 downregulation deregulates multiple mRNA splicing events and leads to deterred cancer cell growth, which is consistent with the impact of PLRG1 repression. Finally, USP42 expression is strongly correlated with that of PLRG1 in non-small-cell lung cancer samples and predicts adverse prognosis in overall survival. As a deubiquitylase capable of dynamically guiding nuclear speckle phase separation and mRNA splicing, USP42 inhibition presents a novel anticancer strategy by targeting phase separation.
| S-EPMC8329168 | biostudies-literature
Project description:The gene transactivation function of nuclear EGFR (nEGFR) has been studied by investigating the genomic co-occupancies of nEGFR and RNA Polymerase II (RNAPII). However, due to RNAPII pausing, the co-recruitment of RNAPII and nEGFR does not necessarily represent productive transactivation. In this study, we integrated gatekeepers of productive transcriptional elongation such as Integrator and Super Elongation Complex (SEC) to interrogate the function of nEGFR. By analyzing publicly available ChIP-seq and RNA-seq data, we aims to 1) explore the function of nEGFR, 2) unravel nEGFR target genes, and 3) discuss potential mechanisms of nEGFR chromatin recruitment. EGF treatment in HeLa cells instigated chromatin recruitment of nEGFR, ERK, RNAPII, Integrator, and SEC in a cluster of 61 EGF-responsive genes. The function of nEGFR was identified as gene-activating rather than gene-repressing. Within the cluster of EGF-responsive genes, nEGFR targeted eleven Immediate Early Genes (IEGs) - JUN, EGR1, JUNB, IER2, KLF2, FOS, FOSL1, RHOB, CCNL1, DUSP2, and DUSP5, which up-regulated >2-fold after EGF stimulation. The promoter of these target genes commonly harbors AT-rich minimal consensus sequences for nEGFR binding. In addition, TCGA data analysis demonstrated positive correlations between EGFR and JUN/FOSL1/RHOB expressions, as well as clinical correlations in specific cancer types. To our knowledge, this is the first study to compare the genome-wide distribution of nEGFR versus Integrator and SEC, providing novel insight into supporting the gene-activating function of nEGFR. We revealed a panel of eleven nEGFR target genes, which concurrently recruited nEGFR, RNAPII, Integrator, and SEC for productive transcriptional elongation.
| S-EPMC5743717 | biostudies-literature
Project description:The plant growth hormone indoleacetic acid (IAA) transcriptionally activates gene expression in plants. Some of the genes whose expression is induced by IAA encode a family of proteins in pea (PS-IAA4 and PS-IAA6) and Arabidopsis (IAA1 and IAA2) that contain putative nuclear localization signals that direct a beta-glucuronidase reporter protein into the nucleus. Pulse-chase and immunoprecipitation experiments have defined the t1/2 of the PS-IAA4 and PS-IAA6 proteins to be 8 and 6 min, respectively. Their most prominent feature is the presence of a beta alpha alpha motif similar to the beta-sheet DNA-binding domain found in prokaryotic repressors of the Arc family. Based on these data, we suggest that plant tissues express short-lived nuclear proteins as a primary response to IAA. We propose that these proteins act as activators or repressors of genes responsible for mediating the various auxin responses.
| S-EPMC42940 | biostudies-other
Project description:Dysregulation of RNA processing contributes to neurodegenerative diseases, especially amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Expansion of an intronic (GGGGCC)n repeat within the C9ORF72 gene is the most common cause of both FTD and ALS (C9-FTD/ALS), characterized with aberrant repeat RNA foci in the nucleus and noncanonical translation-produced dipeptide repeat (DPR) protein inclusions in the cytoplasm. Here we elucidate that the (GGGGCC)n repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics. Moreover, the essential nuclear speckle scaffold protein SRRM2 is sequestered into the poly-GR cytoplasmic inclusions in C9-FTD/ALS mouse model and patient postmortem tissues, exacerbating the nuclear speckle dysfunction. Impaired nuclear speckle integrity induces global exon-skipping and intron retention in human iPSC-derived neurons. Similar alternative splicing changes can be found in patient postmortem tissues. This work identified novel molecular mechanism of global RNA splicing defects by impaired nuclear speckle function in C9-FTD/ALS and revealed novel potential biomarkers or therapeutic targets.
2024-08-23 | GSE248404 | GEO