Reanalysis of TSA-Seq mapping to determine genomic coordinates for speckles-associated domains.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE248644 | GEO | 2023/12/01
REPOSITORIES: GEO
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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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Project description:Nuclear Speckles are large, multi-component condensates in the mammalian nuclei that are thought to be involved in various stages of gene expression, including transcription, splicing, and export. Investigating the direct role of Speckles in these processes have been intractable due to their heterogeneous, multi-component nature. Here we show that Speckles are necessary for the splicing of GC-rich, levelled intron/exon architecture. Acute removal of Speckles leads to a drastic downregulation of GC-rich genes which are clustered within GC-rich isochores. Genes outside these domains are physically away from Speckles and are not affected from loss of Speckles. Animal genomes that do not have GC-rich isochores, do not have GC-rich levelled intron/exon architecture and do not have Speckles. Our results suggest that the expansion of Speckles core proteins’ intrinsically disordered domains during vertebrate evolution facilitated GC-content elevation in Amniotes by creating a condensate necessary to splice the by-products of this process: GC-rich, levelled intron/exon architecture.
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Project description:Nuclear Speckles are large, multi-component condensates in the mammalian nuclei that are thought to be involved in various stages of gene expression, including transcription, splicing, and export. Investigating the direct role of Speckles in these processes have been intractable due to their heterogeneous, multi-component nature. Here we show that Speckles are necessary for the splicing of GC-rich, levelled intron/exon architecture. Acute removal of Speckles leads to a drastic downregulation of GC-rich genes which are clustered within GC-rich isochores. Genes outside these domains are physically away from Speckles and are not affected from loss of Speckles. Animal genomes that do not have GC-rich isochores, do not have GC-rich levelled intron/exon architecture and do not have Speckles. Our results suggest that the expansion of Speckles core proteins’ intrinsically disordered domains during vertebrate evolution facilitated GC-content elevation in Amniotes by creating a condensate necessary to splice the by-products of this process: GC-rich, levelled intron/exon architecture.
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Project description:Nuclear Speckles are large, multi-component condensates in the mammalian nuclei that are thought to be involved in various stages of gene expression, including transcription, splicing, and export. Investigating the direct role of Speckles in these processes have been intractable due to their heterogeneous, multi-component nature. Here we show that Speckles are necessary for the splicing of GC-rich, levelled intron/exon architecture. Acute removal of Speckles leads to a drastic downregulation of GC-rich genes which are clustered within GC-rich isochores. Genes outside these domains are physically away from Speckles and are not affected from loss of Speckles. Animal genomes that do not have GC-rich isochores, do not have GC-rich levelled intron/exon architecture and do not have Speckles. Our results suggest that the expansion of Speckles core proteins’ intrinsically disordered domains during vertebrate evolution facilitated GC-content elevation in Amniotes by creating a condensate necessary to splice the by-products of this process: GC-rich, levelled intron/exon architecture.
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