Genome-wide analyses of XRN1-sensitive targets in osteosarcoma cells identify disease-relevant transcripts containing G-rich motifs

Pashler, Amy L, Towler, Benjamin P, Jones, Christopher I, Haime, Hope J, Burgess, Tom and Newbury, Sarah F (2021) Genome-wide analyses of XRN1-sensitive targets in osteosarcoma cells identify disease-relevant transcripts containing G-rich motifs. RNA, 27 (10). pp. 1265-1280. ISSN 1355-8382

[img] PDF - Published Version
Available under License Creative Commons Attribution-Non-Commercial.

Download (10MB)

Abstract

XRN1 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.

Item Type: Article
Keywords: Ewing sarcoma, RNA degradation, RNA-seq, XRN1, lncRNAs, Bone Neoplasms, Cell Line, Tumor, Child, Computational Biology, Exoribonucleases, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Genome-Wide Association Study, Humans, Microtubule-Associated Proteins, Molecular Sequence Annotation, Nucleotide Motifs, Osteosarcoma, RNA Processing, Post-Transcriptional, RNA Stability, RNA, Long Noncoding, RNA, Messenger, RNA, Neoplasm
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 06 Oct 2021 06:55
Last Modified: 16 Jul 2022 01:00
URI: http://sro.sussex.ac.uk/id/eprint/102131

View download statistics for this item

📧 Request an update