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Regulation of mRNA Levels by Suicidal Introns that Induce Nuclear Decay

ABSTRACT: In eukaryotic cells, inefficient splicing is surprisingly common and leads to degradation of transcripts with retained introns. How pre-mRNAs are committed to nuclear decay is unknown. Here we uncover a mechanism by which intronic transcripts are targeted for nuclear degradation in fission yeast. Surprisingly, sequence elements within “suicidal” introns co-transcriptionally recruit the exosome adaptor Mmi1 not only to degrade unspliced precursor, but also to downregulate levels of the resulting mRNA. Under conditions permissive for fast splicing, Mmi1 is no longer recruited and negative expression regulation is relieved. This mechanism negatively regulates levels of the RNA-helicase DDX5/Dbp2 to ensure cell survival in response to stress. We propose that suicidal introns are maintained because they facilitate regulation of gene expression. We identify multiple novel Mmi1 targets including mRNAs, non-coding RNAs, and sn/snoRNAs. We suggest a general role in RNA regulation for Mmi1 beyond degradation of meiotic transcripts.

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE73144 | GEO | 2015/11/19

SECONDARY ACCESSION(S): PRJNA296069

REPOSITORIES: GEO

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Regulation of mRNA Levels by Suicidal Introns that Induce Nuclear Decay

Project description:In eukaryotic cells, inefficient splicing is surprisingly common and leads to degradation of transcripts with retained introns. How pre-mRNAs are committed to nuclear decay is unknown. Here we uncover a mechanism by which intronic transcripts are targeted for nuclear degradation in fission yeast. Surprisingly, sequence elements within âsuicidalâ introns co-transcriptionally recruit the exosome adaptor Mmi1 not only to degrade unspliced precursor, but also to downregulate levels of the resulting mRNA. Under conditions permissive for fast splicing, Mmi1 is no longer recruited and negative expression regulation is relieved. This mechanism negatively regulates levels of the RNA-helicase DDX5/Dbp2 to ensure cell survival in response to stress. We propose that suicidal introns are maintained because they facilitate regulation of gene expression. We identify multiple novel Mmi1 targets including mRNAs, non-coding RNAs, and sn/snoRNAs. We suggest a general role in RNA regulation for Mmi1 beyond degradation of meiotic transcripts. Two biological replicates of CRAC experiments (Control and Mmi1-HTP). Six RNAseq datasets in total: three biological replicates of wt and delta Mmi1 strain.

2015-11-19 | E-GEOD-73144 | biostudies-arrayexpress

Genome-wide Identification of DEAD-box RNA Helicase Targets Reveals Roles for RNA Secondary Structure Remodeling in mRNA Processing (RNA Pol II ChIP-seq)

Project description:Proper formation of messenger RNA-protein complexes (mRNPs) is critical for accurate gene expression and requires temporal regulation of mRNA structures. RNA helicases are major players that control mRNP/mRNA structures throughout the life of mRNAs. Our group has shown that the DEAD-box RNA helicase Dbp2 in S. cerevisiae is a bona fide RNA helicase in vitro that is required for proper transcription termination and assembly of RNA-binding proteins onto poly(A)+ RNA in vivo. Here, we utilized multiple genome-wide approaches to identify the mRNAs and processing steps targeted by the enzymatic activity of Dbp2. We found that Dbp2 promotes efficient termination of mRNA transcription through remodeling of RNA structures at the 3’ end of mRNAs. This finding elucidates how an RNA helicase regulates gene expression by modulating RNA structures at a genome-wide scale. In addition, Dbp2 facilitates efficient splicing, for which the helicase activity of Dbp2 is required. This reveals a previously uncharacterized role of RNA helicases besides known splicing factors. Overall, our work shows that Dbp2 plays a critical role in pre-mRNA processing and how RNA structure remodeling impacts gene expression.

2019-05-01 | GSE125283 | GEO

Cue-specific remodeling of the neuronal transcriptome through intron retention programs

Project description:We provide a comprehensive map of the subcellular localization of mRNAs in mature neurons and reveal that transcripts stably retaining introns are broadly targeted for nuclear retention. We systematically probed the fate of nuclear transcripts upon neuronal stimulation and found that sub-populations of transcripts are bi-directionally regulated in response to neuronal cues: some are targeted for degradation while others undergo splicing completion to generate fully mature mRNAs which are exported to the cytosol.

2022-08-31 | GSE210071 | GEO

ChIP-Chip

Project description:The regulation of protein-coding and noncoding RNAs is linked to nuclear processes including chromatin modifications and gene silencing. However, the mechanisms that distinguish RNAs and mediate their functions are poorly understood. We describe a nuclear RNA processing network in fission yeast with a core module comprising the Mtr4-like protein, Mtl1, and the zinc finger protein Red1. The Mtl1-Red1 core promotes degradation of mRNAs and noncoding RNAs, and associates with different proteins to assemble heterochromatin via distinct mechanisms. Mtl1 also forms Red1-independent interactions with evolutionarily conserved proteins named Nrl1 and Ctr1, which associate with splicing factors. Whereas Nrl1 targets transcripts with cryptic introns to form heterochromatin at developmental genes and retrotransposons, Ctr1 is required to process intron-containing telomerase RNA. Together with our discovery of widespread cryptic introns, including in noncoding RNAs, these findings reveal unique cellular strategies for recognizing regulatory RNAs and coordinating their functions in response to developmental and environmental cues.

2013-11-21 | E-MTAB-1962 | biostudies-arrayexpress

The faint sausage gene encodes a subunit of the spliceosome-activating Prp19 complex and is required for tracheal branching morphogenesis in Drosophila

Project description:Morphogenesis requires the dynamic regulation of gene expression, including transcription, mRNA maturation and translation. Dysfunction of general components of the splicing machinery can cause surprisingly specific phenotypes, but the basis for these cell-type specific effects is not clear. Here we show that the faint sausage (fas) locus, implicated in epithelial morphogenesis and previously reported to encode a secreted immunoglobulin domain protein, in fact encodes a subunit of the Prp19 complex that is essential for efficient pre-mRNA splicing. Loss of zygotic fas function impairs the efficiency of splicing, associated with widespread retention of introns in mature mRNAs and dramatic changes in gene expression. Surprisingly, despite these general effects, zygotic fas mutants show specific defects in tracheal cell migration. Zygotic fas function becomes essential during late embryogenesis when maternally supplied splicing factors decline. We propose that tracheal branching, which relies on dynamic changes in gene expression, is particularly sensitive for efficient spliceosome function. Our results provide an entry point to study functions of splicing during organogenesis and provide a better understanding of specific disease phenotypes associated with mutations in general splicing factors.

2016-11-18 | E-MTAB-5069 | biostudies-arrayexpress

Schizosaccharomyces pombe

Project description:Regulation of mRNA Levels by Suicidal Introns that Induce Nuclear Decay

| PRJNA296069 | ENA

Genome-wide Identification of DEAD-box RNA Helicase Targets Reveals Roles for RNA Secondary Structure Remodeling in mRNA Processing (Structure-seq)

Project description:Accurate gene expression requires the coordination of RNA processing with assembly of messenger RNA-protein (mRNP) complex. RNA helicases are a class of enzymes that unwind RNA duplexes in vitro and have been are proposed to remodel RNA structure in vivo. Herein, we provide evidence that the DEAD-box protein Dbp2 remodels RNA structure to facilitate efficient pre-mRNA processing in S. cerevisiae. First, we find that Dbp2 associates with the 3’ ends and 3’ splice-sites of mRNAs genome-wide. Using structure-seq to map RNA secondary structure, we find altered secondary structures in dbp2∆ cells that overlap polyadenylation elements and correlate with inefficient termination. We also identify a role for Dbp2 in pre-mRNA splicing and show that both splicing and termination require Dbp2 helicase activity. This reveals that DEAD-box RNA helicases unwind structure in vivo and that structural alteration of pre-mRNA is essential for proper gene expression.

2019-05-01 | GSE106478 | GEO

Genome-wide Identification of DEAD-box RNA Helicase Targets Reveals Roles for RNA Secondary Structure Remodeling in mRNA Processing (iCLIP-seq)

2019-05-01 | GSE106477 | GEO

Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention

Project description:Differentiated cells acquire unique structural and functional traits through coordinated expression of lineage-specific genes. An extensive battery of genes encoding components of the synaptic transmission machinery and specialized cytoskeletal proteins is activated during neurogenesis, but the underlying regulation is not well understood. Here we show that genes encoding critical presynaptic proteins are transcribed at a detectable level in both neurons and non-neuronal cells. However, in non-neuronal cells, the splicing of 3M-bM-^@M-^Y-terminal introns within these genes is repressed by polypyrimidine tract-binding protein (Ptbp1). This inhibits the export of incompletely spliced mRNAs to the cytoplasm and triggers their nuclear degradation. Clearance of these intron-containing transcripts occurs independently of the nonsense-mediated decay (NMD) pathway but requires components of the nuclear RNA surveillance machinery including the nuclear pore-associated protein Tpr and components of the exosome complex. When Ptbp1 expression decreases during neuronal differentiation, the regulated introns are spliced out thus allowing the accumulation of translation-competent mRNAs in the cytoplasm. We propose that this mechanism counters ectopic and precocious expression of functionally linked neuron-specific genes and ensures their coherent activation in the appropriate developmental context. PTBP1 siRNA, PTBP1+PTBP2 siRNA, or control siRNA

2012-07-12 | E-GEOD-37933 | biostudies-arrayexpress

Stability of meiosis-specific messenger RNA provides a novel paradigm for the regulation of meiosis

Project description:Compared to mitosis, much remains to be elucidated about molecular regulation of meiosis, although increasing light has been shed recently on its signal transduction, cell cycle regulation and chromosome dynamics. Here we show that some transcripts required exclusively for meiosis in fission yeast, such as mei4 mRNA encoding a transcription factor or rec8 mRNA encoding a cohesin subunit, are highly unstable if expressed during the mitotic cell cycle. These transcripts carry a cis-acting region responsible for the mitotic instability, which we name DSR. A YTH-family protein encoded by the mmi1 gene is essential for manifestation of their instability. Deletion of mmi1 impairs cell growth severely, apparently due to detriments brought by untimely expression of meiotic messages. Microarray analysis using a temperature-sensitive mmi1 mutant has revealed that at least a dozen of meiosis-specific transcripts are governed by the DSR-mmi1 system. Thus, regulation of mRNA stability appears to play a crucial role in differentiating the mitotic and the meiotic cell cycles. Keywords: Keywards: Time course, Temperature-sensitive mutant, mmi1

2006-07-06 | GSE3314 | GEO

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