RNA-2021-Pashler-1265-80.pdf (9.74 MB)
Genome-wide analyses of XRN1-sensitive targets in osteosarcoma cells identify disease-relevant transcripts containing G-rich motifs
journal contribution
posted on 2023-06-10, 01:19 authored by Amy L Pashler, Benjamin TowlerBenjamin Towler, Chris JonesChris Jones, Hope HaimeHope Haime, Tom Burgess, Sarah NewburySarah NewburyXRN1 is a highly conserved exoribonuclease which degrades uncapped RNAs in a 5'-3' direction. Degradation of RNAs by XRN1 is important in many cellular and developmental processes and is relevant to human disease. Studies in D. melanogaster demonstrate that XRN1 can target specific RNAs, which have important consequences for developmental pathways. Osteosarcoma is a malignancy of the bone and accounts for 2% of all pediatric cancers worldwide. Five-year survival of patients has remained static since the 1970s and therefore furthering our molecular understanding of this disease is crucial. Previous work has shown a down-regulation of XRN1 in osteosarcoma cells; however, the transcripts regulated by XRN1 which might promote osteosarcoma remain elusive. Here, we confirm reduced levels of XRN1 in osteosarcoma cell lines and patient samples and identify XRN1-sensitive transcripts in human osteosarcoma cells. Using RNA-seq in XRN1-knockdown SAOS-2 cells, we show that 1178 genes are differentially regulated. Using a novel bioinformatic approach, we demonstrate that 134 transcripts show characteristics of direct post-transcriptional regulation by XRN1. Long noncoding RNAs (lncRNAs) are enriched in this group, suggesting that XRN1 normally plays an important role in controlling lncRNA expression in these cells. Among potential lncRNAs targeted by XRN1 is HOTAIR, which is known to be up-regulated in osteosarcoma and contributes to disease progression. We have also identified G-rich and GU motifs in post-transcriptionally regulated transcripts which appear to sensitize them to XRN1 degradation. Our results therefore provide significant insights into the specificity of XRN1 in human cells which are relevant to disease.
History
Publication status
- Published
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- Published version
Journal
RNAISSN
1355-8382Publisher
Cold Spring Harbor Laboratory PressExternal DOI
Issue
10Volume
27Page range
1265-1280Event location
United StatesDepartment affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-10-06First Open Access (FOA) Date
2021-10-06First Compliant Deposit (FCD) Date
2021-10-06Usage metrics
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No categories selectedKeywords
Ewing sarcomaRNA degradationRNA-seqXRN1lncRNAsBone NeoplasmsCell LineTumorChildComputational BiologyExoribonucleasesGene Expression RegulationNeoplasticGene Knockdown TechniquesGenome-Wide Association StudyHumansMicrotubule-Associated ProteinsMolecular Sequence AnnotationNucleotide MotifsOsteosarcomaRNA ProcessingPost-TranscriptionalRNA StabilityRNALong NoncodingMessengerNeoplasm
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