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Genome organization around nuclear speckles drives mRNA splicing efficiency

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE247833 | GEO | 2024/03/22

REPOSITORIES: GEO

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SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes

Project description:Splicing is catalyzed by the spliceosome, a compositionally dynamic complex assembled stepwise on pre-mRNA. We reveal links between splicing machinery components and the intrinsically disordered ciliopathy protein SANS. Pathogenic mutations in SANS/USH1G lead to Usher syndrome––the most common cause of deaf-blindness. Previously, SANS was shown to function only in the cytosol and primary cilia. Here, we have uncovered molecular links between SANS and pre-mRNA splicing catalyzed by the spliceosome in the nucleus. We show that SANS is found in Cajal bodies and nuclear speckles, where it interacts with components of spliceosomal subcomplexes such as SF3B1 and the large splicing cofactor SON but also with PRPFs and snRNAs related to the tri-snRNP complex. SANS is required for the transfer of tri-snRNPs between Cajal bodies and nuclear speckles for spliceosome assembly and may also participate in snRNP recycling back to Cajal bodies. SANS depletion alters the kinetics of spliceosome assembly, leading to accumulation of complex A. SANS deficiency and USH1G pathogenic mutations affects splicing of genes related to cell proliferation and USH. Thus, we provide the first evidence that splicing dysregulation may participate in the pathophysiology of Usher syndrome.

2021-05-25 | PXD023942 | Pride

TAF2 condensation in nuclear speckles links basal transcription factor TFIID to RNA splicing [CUT&RUN]

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TAF2 condensation in nuclear speckles links basal transcription factor TFIID to RNA splicing [RNA-Seq]

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Competition between pre-mRNAs for a limiting splicing machinery drives global changes in splicing

Project description:During meiosis in yeast, global splicing efficiency increases. The mechanism for this is relief of competition for the splicing machinery by repression of intron-containing ribosomal protein genes (RPGs). Repression of RPGs with rapamycin also increases splicing efficiency in vegetative cells. Reducing levels of an RPG-dedicated transcription factor globally improves splicing and suppresses the temperature-sensitive growth defect of a spliceosome mutation. These results indicate that the spliceosome is limiting and pre-mRNAs compete with each other. Under these conditions, splicing efficiency of a given pre-mRNA therefore depends on both its concentration and affinity for the limiting splicing factor(s) as well as those of the competing pre-mRNAs. We propose that trans-competition control of splicing helps repress meiotic gene expression in vegetative cells, and promotes efficient meiosis. Competition between RNAs for a limiting factor may be a general condition important for function of a variety of post-transcriptional control mechanisms. Splicing and gene expression profiles of 1) wild type yeast cells treated with rapamycin (2 biological replicates) relative to untreated cells and 2) prp4-1 pGAL-IFH1 (down-regulated expression of IFH1 transcription factor(specific for ribosomal protein genes)) relative to prp4-1 yeast.

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Arabidopsis SME interactome reveals spliceosome components

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Alternative splicing modulation mediated by G-quadruplex structures in MALAT1 lncRNA

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2022-02-17 | PXD026386 | Pride

Son Maintains Accurate Splicing of Pre-mRNAs Encoding Chromatin Modifiers

Project description:Exon and expression analysis of HeLa cells after knockdown of SON Serine-arginine-rich (SR) proteins play a key role in alternative pre-mRNA splicing in eukaryotes. Our laboratory recently showed that a large SR protein called Son has unique repeat motifs that are essential for maintaining the subnuclear organization of pre-mRNA processing factors in nuclear speckles. Motif analysis of Son highlights putative RNA interaction domains that suggest a direct role for Son in pre-mRNA splicing. A genome-wide screen was performed to identify putative human transcription and splicing targets of Son. HeLa cells were transfected with siRNA against SON or a control siRNA (siLuciferase) for 48 hours. Five biological replicates were used for each condition.

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Son Maintains Accurate Splicing of Pre-mRNAs Encoding Chromatin Modifiers

2011-12-22 | GSE28672 | GEO

Competition between pre-mRNAs for a limiting splicing machinery drives global changes in splicing

2013-10-22 | GSE44219 | GEO

Quality control of spliced mRNAs requires the shuttling SR-proteins Gbp2 and Hrb1

Project description:Eukaryotic cells have to prevent the export of unspliced pre-mRNAs until intron removal is completed to avoid the expression of aberrant and potentially harmful proteins. Only mature RNAs associate with the export receptor Mex67 (mammalian TAP) and enter the cytoplasm. The underlying nuclear quality control mechanisms are still unclear. Here we show that two shuttling SR-proteins Gbp2 and Hrb1 are key surveillance factors for the selective export of spliced mRNAs in yeast. Their absence leads to the significant leakage of unspliced pre-mRNAs into the cytoplasm. They bind to pre-mRNAs and the spliceosome during splicing, where they are necessary for the surveillance of splicing and the stable binding of the TRAMP-complex to the spliceosome-bound transcripts. Faulty transcripts are marked for their degradation at the nuclear exosome. On correct mRNAs the SR-proteins recruit Mex67 upon completion of splicing to allow a quality controlled nuclear export. Altogether, these data identify a role for shuttling SR-proteins in mRNA surveillance and nuclear mRNA quality control. 6 samples, i.e. 2 replicates per protein Gbp2, Hrb1 and Npl3

2013-12-04 | E-GEOD-52808 | biostudies-arrayexpress

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