MRNA export factors store nascent transcripts within nuclear speckles as an adaptive response to transient global inhibition of transcription.
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ABSTRACT:
PROVIDER: PRJNA761338 | ENA |
REPOSITORIES: ENA
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Project description:Several transcription inhibitors have been developed as cancer therapies. However, they show modest clinical activity highlighting that our understanding of the cellular response to transcriptional inhibition remains incomplete. Here we report that potent inhibitors of transcription not only impact mRNA output, but also markedly impair mRNA transcript localisation and nuclear export. We demonstrate that retention of newly transcribed mRNA in nuclear speckles is an adaptive response to chemically distinct transcriptional inhibitors. Retained transcripts are fully processed and accumulate in proportion to the expression level of the genes from which they emanate. The TREX mRNA export complex plays an integral role in directing nascent transcripts to nuclear speckles where they are bound to NXF1, protected from degradation, and poised for rapid export following re-initiation of transcription. Our findings provide new insights into the crosstalk between transcription and mRNA export, with important implications for drugs aiming to inhibit transcription for therapeutic gain.
2025-02-13 | GSE183570 | GEO
Project description:Several transcription inhibitors have been developed as cancer therapies. However, they show modest clinical activity highlighting that our understanding of the cellular response to transcriptional inhibition remains incomplete. Here we report that potent inhibitors of transcription not only impact mRNA output, but also markedly impair mRNA transcript localisation and nuclear export. We demonstrate that retention of newly transcribed mRNA in nuclear speckles is an adaptive response to chemically distinct transcriptional inhibitors. Retained transcripts are fully processed and accumulate in proportion to the expression level of the genes from which they emanate. The TREX mRNA export complex plays an integral role in directing nascent transcripts to nuclear speckles where they are bound to NXF1, protected from degradation, and poised for rapid export following re-initiation of transcription. Our findings provide new insights into the crosstalk between transcription and mRNA export, with important implications for drugs aiming to inhibit transcription for therapeutic gain.
2025-02-13 | GSE183569 | GEO
Project description:Several transcription inhibitors have been developed as cancer therapies. However, they show modest clinical activity highlighting that our understanding of the cellular response to transcriptional inhibition remains incomplete. Here we report that potent inhibitors of transcription not only impact mRNA output, but also markedly impair mRNA transcript localisation and nuclear export. We demonstrate that retention of newly transcribed mRNA in nuclear speckles is an adaptive response to chemically distinct transcriptional inhibitors. Retained transcripts are fully processed and accumulate in proportion to the expression level of the genes from which they emanate. The TREX mRNA export complex plays an integral role in directing nascent transcripts to nuclear speckles where they are bound to NXF1, protected from degradation, and poised for rapid export following re-initiation of transcription. Our findings provide new insights into the crosstalk between transcription and mRNA export, with important implications for drugs aiming to inhibit transcription for therapeutic gain.
2025-02-13 | GSE284174 | GEO
Project description:mRNA export factors store nascent transcripts within nuclear speckles as an adaptive response to transient global inhibition of transcription.
| PRJNA761339 | ENA
Project description:mRNA export factors store nascent transcripts within nuclear speckles as an adaptive response to transient global inhibition of transcription.
| PRJNA761329 | ENA
Project description:mRNA export factors store nascent transcripts within nuclear speckles as an adaptive response to transient global inhibition of transcription [SLAM-seq]
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Project description:This SuperSeries is composed of the SubSeries listed below.
2025-02-12 | GSE183571 | GEO
Project description:Small RNA silencing pathways protect genome integrity in part through establishing heterochromatin at transposon loci. In animals, this process requires piRNA-guided targeting of nuclear PIWI proteins to nascent transcripts. The molecular events contributing to heterochromatin formation upon PIWI binding to nascent RNA, a transient molecule at chromatin, are unknown. Here, we identify SFINX, a protein complex that is required for Piwi-mediated co-transcriptional silencing in Drosophila. It consists of Nxf2—a variant of the nuclear RNA export factor Nxf1/Tap, the mRNA export co-factor Nxt1/p15, and the Piwi-associated protein Panoramix. In the absence of Nxf2, Panoramix is targeted for degradation and piRNA-loaded Piwi is unable to establish heterochromatin. Consequently, nxf2 mutants exhibit severe transposon de-repression and are sterile. We show that within SFINX, Panoramix connects to the heterochromatin machinery while Nxf2 enables target silencing via nascent RNA. Thus, the Nxf2-Nxt1 heterodimer—despite having originated from core mRNA export machinery—has been repurposed for heterochromatin formation. Our data establish an unexpected link between nuclear small RNA biology and NXF-variants, which are widespread in animal lineages, but mostly lack ascribed functions.
2019-06-12 | PXD011201 | Pride
Project description:Nuclear speckles are dynamic nuclear bodies characterized by high local concentrations of RNA binding proteins and specific non-coding RNAs. Although the contents of speckles suggest multifaceted roles in regulating chromatin dynamics and gene expression, the overarching biological function(s) of nuclear speckles remain enigmatic. In this study, we investigate speckle compositional variation in human cancer, finding two main speckle compositional states based on RNA expression of speckle-resident proteins. One cancer speckle state was more similar to normal adjacent tissues, while the other was dissimilar from normal tissue, and thus considered an aberrant cancer speckle state. We link the aberrant speckle state to altered speckle positioning within the nucleus, to elevation of the TREX RNA export complex, and to worse patient outcomes in clear cell renal cell carcinoma (ccRCC). ccRCC is typified by hyperactivation of the HIF-2a transcription factor, and we demonstrate that HIF-2a drives physical association of a select subset of its target genes with nuclear speckles depending on HIF-2a's two speckle targeting motifs (STMs) defined in this study. STMs are highly enriched among transcription factors, suggesting that DNA-speckle targeting may be a general mechanism of gene regulation and providing a resource of candidate speckle-targeting factors. Via integration of tissue culture functional studies with tumor genomic and imaging analysis, we show that HIF-2a gene regulatory programs are impacted by speckle compositional state and by abrogation of speckle targeting abilities of HIF-2a. These findings suggest that, in ccRCC, a key biological function of nuclear speckles is to modulate expression of a specific subset of HIF-2a-regulated target genes that, in turn, influence patient outcomes. Beyond ccRCC, tumor speckle compositional states broadly correlate with altered functional pathways and expression of speckle-associated gene neighborhoods, exposing a general link between nuclear speckles and gene expression dysregulation in human cancer.
2024-09-03 | GSE248706 | GEO
Project description:Nuclear speckles are dynamic nuclear bodies characterized by high local concentrations of RNA binding proteins and specific non-coding RNAs. Although the contents of speckles suggest multifaceted roles in regulating chromatin dynamics and gene expression, the overarching biological function(s) of nuclear speckles remain enigmatic. In this study, we investigate speckle compositional variation in human cancer, finding two main speckle compositional states based on RNA expression of speckle-resident proteins. One cancer speckle state was more similar to normal adjacent tissues, while the other was dissimilar from normal tissue, and thus considered an aberrant cancer speckle state. We link the aberrant speckle state to altered speckle positioning within the nucleus, to elevation of the TREX RNA export complex, and to worse patient outcomes in clear cell renal cell carcinoma (ccRCC). ccRCC is typified by hyperactivation of the HIF-2a transcription factor, and we demonstrate that HIF-2a drives physical association of a select subset of its target genes with nuclear speckles depending on HIF-2a's two speckle targeting motifs (STMs) defined in this study. STMs are highly enriched among transcription factors, suggesting that DNA-speckle targeting may be a general mechanism of gene regulation and providing a resource of candidate speckle-targeting factors. Via integration of tissue culture functional studies with tumor genomic and imaging analysis, we show that HIF-2a gene regulatory programs are impacted by speckle compositional state and by abrogation of speckle targeting abilities of HIF-2a. These findings suggest that, in ccRCC, a key biological function of nuclear speckles is to modulate expression of a specific subset of HIF-2a-regulated target genes that, in turn, influence patient outcomes. Beyond ccRCC, tumor speckle compositional states broadly correlate with altered functional pathways and expression of speckle-associated gene neighborhoods, exposing a general link between nuclear speckles and gene expression dysregulation in human cancer.
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