RNA localization to nuclear speckles follows splicing logic
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE318459 | GEO | 2026/02/05
REPOSITORIES: GEO
Similar Datasets
Project description:Nuclear speckles, a type of membraneless nuclear organelle in higher eukaryotic cells, play a vital role in gene expression regulation. Using the reverse transcription-based RBP binding sites sequencing (ARTR-seq) method, we study human transcripts associated with nuclear speckles. We identify three gene groups whose transcripts demonstrate different speckle localization properties and dynamics – stably enriched in nuclear speckle post-transcriptionally, transiently enriched in speckles at the pre-mRNA stage co-transcriptionally, and not enriched in speckles. We show that nuclear speckles specifically facilitate splicing of speckle-enriched transcripts. We further reveal RNA sequence features contributing to transcript speckle localization, underscoring a tight interplay between genome organization, RNA cis-elements, and transcript speckle enrichment, and connecting transcript speckle localization with splicing logic. Finally, we show that speckles can act as hubs for the regulated retention of introns during cellular stress. Collectively, our data highlight a role of nuclear speckles in both co- and post-transcriptional splicing regulation.
2024-09-05 | GSE255207 | GEO
Project description:Nuclear speckles, a type of membraneless nuclear organelle in higher eukaryotic cells, play a vital role in gene expression regulation. Using the reverse transcription-based RBP binding sites sequencing (ARTR-seq) method, we study human transcripts associated with nuclear speckles. We identify three gene groups whose transcripts demonstrate different speckle localization properties and dynamics – stably enriched in nuclear speckle post-transcriptionally, transiently enriched in speckles at the pre-mRNA stage co-transcriptionally, and not enriched in speckles. We show that nuclear speckles specifically facilitate splicing of speckle-enriched transcripts. We further reveal RNA sequence features contributing to transcript speckle localization, underscoring a tight interplay between genome organization, RNA cis-elements, and transcript speckle enrichment, and connecting transcript speckle localization with splicing logic. Finally, we show that speckles can act as hubs for the regulated retention of introns during cellular stress. Collectively, our data highlight a role of nuclear speckles in both co- and post-transcriptional splicing regulation.
2024-09-05 | GSE255206 | GEO
Project description:RNA localization to nuclear speckles follows splicing logic
| PRJNA1418765 | ENA
Project description:The nucleus is highly organized such that factors involved in transcription and processing of distinct classes of RNA are organized within specific nuclear bodies. One example is the nuclear speckle, which is defined by high concentrations of protein and non-coding RNA regulators of pre-mRNA splicing. What functional role, if any, speckles might play in the process of mRNA splicing remains unknown. Here we show that genes localized near nuclear speckles display higher spliceosome concentrations, increased spliceosome binding to their pre-mRNAs, and higher co-transcriptional splicing levels relative to genes that are located farther from nuclear speckles. We show that directed recruitment of a pre-mRNA to nuclear speckles is sufficient to increase mRNA splicing levels. Finally, we show that gene organization around nuclear speckles is highly dynamic with differential localization between cell types corresponding to differences in splicing efficiency. Together, our results integrate the longstanding observations of nuclear speckles with the biochemistry of mRNA splicing and demonstrate a critical role for dynamic 3D spatial organization of genomic DNA in driving spliceosome concentrations and controlling the efficiency of mRNA splicing.
2024-03-22 | GSE247833 | GEO
Project description:Nuclear speckles are membraneless organelles that act as active splicing hubs especially at sites of high transcription. Emerging views of this dynamic subnuclear structure place it as a hub of RNA processing, impacting steps from transcription to export. To manage this complex microcosm of RNA metabolism, nuclear speckles also require kinases and phosphorylation to execute their functions. The nuclear speckle-localized kinase, TAOK2, mediates the splicing and export of viral transcripts at the nuclear speckle, but its role in the processing of cellular transcripts was unknown. We used siRNA knockdown of TAOK2 and assessed RNA transcripts in both whole cell and nucleocytoplasmic fractions to characterize the complete endogenous effects of TAOK2. We found that TAOK2 knockdown impacts over 10% of the transcriptome, through changes in alternative splicing, export and transcript abundance. Cellular and biochemical phosphoproteomics further revealed nuclear speckle scaffolding proteins SRRM1 and SRRM2 as potential direct phosphorylation targets of TAOK2, mediating its large effects on speckle integrity and speckle-localized splicing. Indeed, knockdown of TAOK2 perturbs almost all speckle-resident serine/arginine (SR)-rich proteins while leaving heterogeneous ribonucleoproteins unperturbed. Altogether, we propose that phosphorylation of SRRM1/2 by TAOK2 plays a structural maintenance role that impacts SR protein-driven exon inclusion at the nuclear speckle.
2026-02-05 | GSE318441 | 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.
2024-09-03 | GSE248710 | 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.
2024-09-03 | GSE248705 | 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.
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.
2024-09-03 | GSE248709 | 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.
2024-09-03 | GSE248708 | GEO