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Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations

ABSTRACT: RNA polymerase III (Pol III) activity in cancer is linked to the production of small noncoding (nc)RNAs that are otherwise silent in most tissues. snaR-A (small NF90-associated RNA isoform A) - a hominid-specific ncRNA shown to enhance cell proliferation, migration, and invasion - is a cancer-emergent Pol III product that remains largely uncharacterized despite promoting growth phenotypes. Here, we applied a combination of genomic and biochemical approaches to predict the biogenesis and subsequent protein interactions of snaR-A to better understand its role as a putative driver of cancer progression. By profiling the chromatin landscapes across a multitude of primary tumor types, we show that predicted snaR-A upregulation is broadly linked with unfavorable outcomes among cancer patients. At the molecular level, we unexpectedly discover widespread interactions between snaR-A and mRNA splicing factors, including SF3B2 - a core component of the U2 small nuclear ribonucleoprotein (snRNP). We find that SF3B2 levels are sensitive to high snaR-A abundance, and that depletion of snaR-A alone is sufficient to decrease intron retention levels across subpopulations of mRNA enriched for U2 snRNP occupancy. snaR-A sensitive genes are characterized by high GC content, close spatial proximity to nuclear bodies concentrated in pre-mRNA splicing factors, and functionally enriched for proteins involved in deacetylation and autophagy. We highlight examples of splicing resolution and increased protein levels following snaR-A depletion for a wide-ranging set of factors, suggesting snaR-A-driven splicing defects may have far-reaching effects that re-shape the cellular proteome. These findings help clarify the molecular activities and consequences of snaR-A express- ion in cancer, and altogether establish a novel mechanism through which Pol III overactivity may promote tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271057 | GEO | 2024/07/24

REPOSITORIES: GEO

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Project description:Purpose: Small interfering RNA (siRNA)-mediated knockdown of SF3B2, a component of U2 snRNP subcomplex in the spliceosome, suppresses innate immune gene expression. To examine whether pladienolide B, a pre-mRNA inhibitor, phenocopies SF3BP2 knockdown, we compared the RNA-seq profiles of SF3B2-depleted and pladienolide B-treated PC3 cells. Method: Total RNAs were extracted from the cells and treated with DNase I. After RNA-seq libraries were constructed, next-generation sequencing and Differential Expressed Gene (DEG) analysis were performed. The library was sequenced on an Illumina NextSeq 6000 as paired-end 101 bp reads. The sequence reads were aligned to the GRCh38 reference genome using HISAT2 version 2.1.0, Bowtie2 2.3.5.1. All reads were assembled with StringTie software version 2.1.3b, using annotated genes from the NCBI database. Low quality transcripts are filtered. Afterwards, TMM Normalization are performed. Statistical analysis is performed using Fold Change, exactTest using edgeR per comparison pair. The significant results are selected on conditions of |fc|>=2 & exactTest raw p-value<0.05. DEG analysis was performed on 3 comparisons pairs using edgeR. The results showed 11,306 genes which satisfied |fc|>=2 & exactTest raw p-value<0.05 conditions in at least one of comparison pairs. For Enrichment test which based on Gene Ontology (GO) DB was conducted with significant gene list using g:Profiler tool. Result: Gene signatures of SF3B2-depleted cells were compared with those of control siRNA-treated cells. GO analysis of the down-regulated genes in SF3B2-depleted cells identified GO terms related with innate immunity. Next, gene signatures of pladienolide B-treated cells were compared with those of DMSO-treated cells. GO analysis of genes altered in pladienolide B-treated cells identified GO terms related with RNA splicing. However, innate immunity-related GO terms were classified statistically not significant. Conclusion: These observations indicate that SF3B2 knockdown and pladienolide B differentially affect the gene expression signature in PC3 cells.

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Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations

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