Stress-induced splicing activation of immediate early genes by nuclear speckle reorganization [ANI]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA752091 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15343059_1.fastq.gz | Fastqsanger.gz | |||
| SRR15343059_2.fastq.gz | Fastqsanger.gz | |||
| SRR15343061_1.fastq.gz | Fastqsanger.gz | |||
| SRR15343061_2.fastq.gz | Fastqsanger.gz | |||
| SRR15343063_1.fastq.gz | Fastqsanger.gz |
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Project description:Stress-induced splicing activation of immediate early genes by nuclear speckle reorganization
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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 | GSE231520 | 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: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
Project description:Recent findings indicate that nuclear speckles, a distinct type of nuclear body, interact with certain chromatin regions in a ground state. Here, we report that the chromatin structural factors CTCF and cohesin are required for full ground-state association between DNA and nuclear speckles. We identified a putative speckle targeting motif (STM) within cohesin subunit RAD21 and demonstrated that the STM is required for chromatin-nuclear speckle association, disruption of which impaired induction of speckle-associated genes. Depletion of the cohesin-releasing factor WAPL, which stabilizes cohesin on chromatin and reinforces DNA–speckle contacts, results in enhanced inducibility of speckle-associated genes. Additionally, we observed disruption of chromatin–nuclear speckle association in patient-derived cells with Cornelia de Lange syndrome, a congenital neurodevelopmental disorder involving defective cohesin pathways. In summary, our findings reveal a mechanism for establishing the ground state of chromatin–speckle association and promoting gene inducibility, with relevance to human disease.
2024-11-07 | GSE248103 | GEO
Project description:Nuclear speckles are prominent nuclear bodies that contain a myriad of factors involved in gene expression. The role of nuclear speckles as activating transcriptional compartments is emerging. However, the extent that the association between speckles and DNA is regulatable, and the mechanisms that govern regulated speckle association are currently unclear. Using DNA- and RNA-FISH, we show that speckle association can be mediated by the p53 transcription factor, finding that p53 activation drives speckle association of specific p53 transcriptional targets. Analysis of a key p53 target, p21, revealed an increase in nascent transcripts at speckle-adjacent transcription sites, supporting a role for speckles in amplifying transcriptional output. Importantly, p53-regulated speckle association of p21 did not depend on transcriptional activation, demonstrating that speckle association is not merely a consequence of gene expression. In contrast, speckle association of p21 did require DNA binding functions of p53, providing a mechanism for the specificity by which speckle association is regulated. Beyond p21, a substantial subset of p53 targets have p53-regulated speckle association, while other p53 targets do not, and we find that genomic context is highly deterministic of which target genes have regulated speckle association. These findings reveal a novel means by which transcription factors may control gene expression and provide a mechanism for the specificity of regulated speckle association.
2021-01-04 | GSE154095 | GEO
Project description:The interchromatin space in the cell nucleus contains various membrane-less nuclear bodies. Recent findings indicate that nuclear speckles, comprising a distinct nuclear body, exhibit interactions with certain chromatin regions in a ground state. Key questions are how this ground state of chromatin-nuclear speckle association is established and what are the gene regulatory roles of this layer of nuclear organization. We report here that chromatin structural factors CTCF and cohesin are required for full ground state association between DNA and nuclear speckles. Disruption of ground state DNA-speckle contacts via either CTCF depletion or cohesin depletion had minor effects on basal level expression of speckle-associated genes, however we show strong negative effects on stimulus-dependent induction of speckle-associated genes. We identified a putative speckle targeting motif (STM) within cohesin subunit RAD21 and demonstrated that the STM is required for chromatin-nuclear speckle association. In contrast to reduction of CTCF or RAD21, depletion of the cohesin releasing factor WAPL stabilized cohesin on chromatin and DNA-speckle contacts, resulting in enhanced inducibility of speckle-associated genes. In addition, we observed disruption of chromatin-nuclear speckle association in patient derived cells with Cornelia de Lange syndrome (CdLS), a congenital neurodevelopmental diagnosis involving defective cohesin pathways, thus revealing nuclear speckles as an avenue for therapeutic inquiry. In summary, our findings reveal a mechanism to establish the ground organizational state of chromatin-speckle association, to promote gene inducibility, and with relevance to human disease.
2024-11-08 | GSE248102 | GEO