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LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity [iCLIP]

ABSTRACT: RNA splicing plays a critical role in post-transcriptional gene regulation. Exponential expansion of intron length poses a challenge for accurate splicing. Little is known about how cells prevent inadvertent and often deleterious expression of intronic elements due to cryptic splicing. In this study, we identify hnRNPM as an essential RNA binding protein that suppresses cryptic splicing through binding to deep introns, preserving transcriptome integrity. Long interspersed nuclear elements (LINEs) harbor large amounts of pseudo splice sites in introns. hnRNPM preferentially binds at intronic LINEs and represses LINE-containing pseudo splice site usage for cryptic splicing. Remarkably, a subgroup of the cryptic exons can form long dsRNAs through base-pairing of inverted Alu transposable elements scattered in between LINEs and trigger interferon immune response, a well-known antiviral defense mechanism. Notably, these interferon-associated pathways are found to be upregulated in hnRNPM-deficient tumors, which also exhibit elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity. Targeting hnRNPM in tumors may be used to trigger an inflammatory immune response thereby boosting cancer surveillance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227048 | GEO | 2024/05/29

REPOSITORIES: GEO

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LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity [RNA-seq]

Project description:RNA splicing plays a critical role in post-transcriptional gene regulation. Exponential expansion of intron length poses a challenge for accurate splicing. Little is known about how cells prevent inadvertent and often deleterious expression of intronic elements due to cryptic splicing. In this study, we identify hnRNPM as an essential RNA binding protein that suppresses cryptic splicing through binding to deep introns, preserving transcriptome integrity. Long interspersed nuclear elements (LINEs) harbor large amounts of pseudo splice sites in introns. hnRNPM preferentially binds at intronic LINEs and represses LINE-containing pseudo splice site usage for cryptic splicing. Remarkably, a subgroup of the cryptic exons can form long dsRNAs through base-pairing of inverted Alu transposable elements scattered in between LINEs and trigger interferon immune response, a well-known antiviral defense mechanism. Notably, these interferon-associated pathways are found to be upregulated in hnRNPM-deficient tumors, which also exhibit elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity. Targeting hnRNPM in tumors may be used to trigger an inflammatory immune response thereby boosting cancer surveillance.

2024-05-29 | GSE227047 | GEO

Cell-type restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing

Project description:Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein hnRNPM promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial-mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFb signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFb-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44s splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial-splicing regulator that binds to the same cis-regulatory RNA elements and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program. RNAseq for control, hnRNPM siRNA treated lung metastatic LM2 clonal line, derived from the mesenchymal MDA-MB-231 cells

2014-06-03 | E-GEOD-57243 | biostudies-arrayexpress

Alternative RNA Stuctures Formed During Transcription Depend on Elongation Rate and Modify RNA processing

Project description:Most RNA processing occurs co-transcriptionally. We interrogated nascent pol II transcripts by chemical and enzymatic probing, and determined how the “nascent RNA structureome” relates to splicing, A-I editing and transcription speed. RNA folding within introns and steep structural transitions at splice sites are associated with efficient co-transcriptional splicing. A slow pol II mutant elicits extensive remodeling into more folded conformations with increased A-I editing. Introns that become more structured at their 3’ splice sites get co-transcriptionally excised more efficiently. Slow pol II altered folding of intronic Alu elements where cryptic splicing and intron retention are stimulated, an outcome mimicked by UV which decelerates transcription. Slow transcription also remodeled RNA folding around alternative exons in distinct ways that predict whether skipping or inclusion is favored, even though it occurs post-transcriptionally. Hence co-transcriptional RNA folding modulates post-transcriptional alternative splicing. In summary the plasticity of nascent transcripts has widespread effects on RNA processing.

2021-02-09 | GSE149018 | GEO

Intronic tRNAs of mitochondrial origin regulate constitutive and alternative splicing

Project description:Background: The presence of nuclear mitochondrial DNA (numtDNA) has been reported within several nuclear genomes. Next to mitochondrial protein coding genes, numtDNA sequences also encode for mitochondrial tRNA genes. However, the biological roles of numtDNA, remain elusive. Results: Employing in silico analysis we identify 281 mitochondrial tRNA homologs in the human genome, which we term nimtRNAs (nuclear intronic mitochondrial-derived tRNAs), being contained within introns of 76 nuclear host genes. Despite base changes in nimtRNAs when compared to their mtRNA homologs, a canonical tRNA cloverleaf structure is maintained. To address potential functions of intronic nimtRNAs, we insert them into introns of constitutive and alternative splicing reporters and demonstrate that nimtRNAs promote pre-mRNA splicing, dependent on number and positioning of nimtRNA genes and splice site recognition efficiency. A mutational analysis reveals that the nimtRNA cloverleaf structure is required for the observed splicing increase. Utilizing a CRISPR/Cas9 approach we show that a partial deletion of a single endogenous nimtRNALys within intron 28 of the PPFIBP1 gene decreases inclusion of the downstream located exon 29 of the PPFIBP1 mRNA. By employing a pull-down approach followed by mass spectrometry, a 3’-splice site associated protein network is identified, including KHDRBS1, which we show directly interacts with nimtRNATyr by an electrophoretic mobility shift assay. Conclusions: We propose that nimtRNAs, along with associated protein factors, can act as a novel class of intronic splicing regulatory elements in the human genome by participating in the regulation of splicing.

2020-10-28 | PXD022204 | Pride

Recursive splicing in long vertebrate genes

Project description:Recent studies have shown that expression of many genes with exceptionally long introns in the mammalian brain can be perturbed by regulatory factors linked to neurodevelopmental or neurodegenerative disorders1-3, suggesting unique regulatory mechanisms. Here we identify functional recursive splice sites (RSS) in long introns of genes expressed in the brain. These RSS are highly conserved in genes with extreme length across diverse vertebrate species and permit step-wise removal of long introns via recursive splicing. Recursive splicing requires initial definition of a “recursive exon” that is located downstream of RSS, and most often contains premature stop codons. Moreover, we show that RSS create a splicing switch driven by splice site competition in order to distinguish primary mRNA isoforms from alternative isoforms that are prevalent in long genes. The recursive exon is not detectable in the dominant mRNA isoform due to recursive splicing, but is completely included when cryptic promoters or other cryptic exons are used. Thus, by coupling inclusion of recursive exons with the use of cryptic elements, RSS act to distinguish new mRNA isoforms emerging from long genes.

| EGAS00001001170 | EGA

Cell-type restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing

2014-06-03 | GSE57243 | GEO

HNRNPM-regulated splicing dependencies in prostate cancer [eCLIP-Seq]

Project description:Cancer cells are differentially dependent on the splicing machinery compared to normal untransformed cells. The splicing machinery thus presents a potential therapeutic target in cancer. To identify splicing factors important for prostate cancer cell (PCa) growth, we performed an unbiased pooled shRNA screen in in vitro passaged cells and in vivo xenografted PCa tumors. Our screen revealed HNRNPM as a potential regulator of PCa cell growth. RNA- and eCLIP- sequencing data suggest that HNRNPM is bound to key homeostatic genes, and that loss of HNRNPM binding in a subset of these genes results in aberrant exon inclusion and exon back-splicing events in target transcripts. In mis-spliced transcripts, HNRNPM appears to preferentially bind to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM dependent splicing events using antisense oligonucleotides was sufficient to inhibit cell growth in HNRNPM expressing cells, suggesting that inhibition of cell growth in HNRNPM deficient cells likely has a multi-genic component. Taken together, our data reveal a role for HNRNPM in regulating PCa cell growth, and also as a potential therapeutic target in PCa.

2019-12-25 | GSE113783 | GEO

HNRNPM-regulated splicing dependencies in prostate cancer [RNA-Seq]

2019-12-25 | GSE113782 | GEO

Co-regulation of alternative splicing by hnRNPM and ESRP1 during EMT

Project description:The epithelial-mesenchymal transition (EMT) is a fundamental developmental process that is abnormally activated in cancer metastasis. Dynamic changes in alternative splicing occur during EMT. ESRP1 and hnRNPM are splicing regulators that promote an epithelial splicing program and a mesenchymal splicing program, respectively. The functional relationships between these splicing factors in the genome-scale remain elusive. Comparing alternative splicing targets of hnRNPM and ESRP1 revealed that they co-regulate a set of cassette exon events, with the majority showing discordant splicing regulation. hnRNPM discordantly regulated splicing events show a positive correlation with splicing during EMT while concordant splicing events do not, highlighting the antagonistic role of hnRNPM and ESRP1 during EMT. Motif enrichment analysis near co-regulated exons identifies guanine-uridine rich motifs downstream of hnRNPM-repressed and ESRP1-enhanced exons, supporting a model of competitive binding to these cis-elements to antagonize alternative splicing. The set of co-regulated exons are enriched in genes associated with cell-migration and cytoskeletal reorganization, which are pathways associated with EMT. Splicing levels of co-regulated exons are associated with breast cancer patient survival and correlate with gene sets involved in EMT and breast cancer subtypes. In conclusion, hnRNPM and ESRP1 co-regulate antagonistically a set of alternative splicing events that occur during EMT. This regulation is likely mediated through competition for the same intronic binding sites downstream of variable exons. hnRNPM and ESRP1 regulated splicing events are associated with breast cancer survival.

2018-08-01 | GSE112516 | GEO

Profiling lariat intermediates reveals genetic determinants of early and late co-transcriptional splicing

Project description:Long introns with short exons in vertebrate genes are thought to require spliceosome assembly across exons (exon definition), rather than introns, thereby requiring transcription of an exon to splice an upstream intron. Here, we developed CoLa-seq (co-transcriptional lariat sequencing) to investigate the timing and determinants of co-transcriptional splicing genome wide. Unexpectedly, 90% of all introns, including long introns, can splice before transcription of a downstream exon, indicating that exon definition is not obligatory for most human introns. Still, splicing timing varies dramatically across introns, and various genetic elements determine this variation. Strong U2AF2 binding to the polypyrimidine tract predicts early splicing, explaining exon definition-independent splicing. Together, our findings question the essentiality of exon definition and reveal features beyond intron and exon length that are determinative for splicing timing.

2022-11-26 | GSE204834 | GEO

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