Landscape of Chimeric RNAs in Non-Cancerous Cells

Abstract

Gene fusions and their products (RNA and protein) have been traditionally recognized as unique features of cancer cells and are used as ideal biomarkers and drug targets for multiple cancer types. However, recent studies have demonstrated that chimeric RNAs generated by intergenic alternative splicing can also be found in normal cells and tissues. In this study, we aim to identify chimeric RNAs in different non-neoplastic cell lines and investigate the landscape and expression of these novel candidate chimeric RNAs. To do so, we used HEK-293T, HUVEC, and LO2 cell lines as models, performed paired-end RNA sequencing, and conducted analyses for chimeric RNA profiles. Several filtering criteria were applied, and the landscape of chimeric RNAs was characterized at multiple levels and from various angles. Further, we experimentally validated 17 chimeric RNAs from different classifications. Finally, we examined a number of validated chimeric RNAs in different cancer and non-cancer cells, including blood from healthy donors, and demonstrated their ubiquitous expression pattern.

Functional and regulatory impact of chimeric RNAs in human normal and cancer cells

“…Further, improving these computational tools, validating the functional effects of individual chimeric RNAs in cancer cell lines, and conducting clinical trials could revolutionize the precision oncologybased treatment approaches. Recent studies identified a vast amount of chimeric RNAs in healthy human tissues and normal cells (Babiceanu et al, 2016;Chen et al, 2021;Singh et al, 2020). Chimeric RNAs could be generated by cis-SAGe and trans-splicing in normal human cells .…”

“…However, only a small fraction of chimeric RNAs were validated as functional (Shi et al, 2021; Sun & Li, 2022). Further, the analysis of human transcriptome data from different normal tissues reveals that chimeric RNAs are also prevalent in healthy tissues (Babiceanu et al, 2016; Chen et al, 2021; Singh et al, 2020). However, their functional role in normal tissues is still not clear.…”

Chimeric RNA RRM2-C2orf48 plays an oncogenic role in the development of NNK-induced lung cancer

“…Chimeric RNAs have been found to be generated from trans- splicing and cis -splicing between adjacent genes ( cis -SAGe), without genomic aberrations. 22 Recent studies have suggested that chimeric RNAs generated by cis -SAGe play a potentially important role in normal biological functions in humans. 23 There have been few studies of cis -SAGe chimeric RNAs because only a small number of cis -spliced RNA chimeras have been experimentally confirmed in mammalian cells.…”

Discovery of A Polymorphic Gene Fusion via Bottom-Up Chimeric RNA Prediction

“…These findings have been further supplemented by read-through chimeras such as SLC45A3-ELK4 (7) and chimeras such as ASTN2-PAPPAAS (8), which are produced without noted changes to subject DNA and have demonstrated functions relevant to cancer pathogenesis. There has been a significant effort to catalogue chimeric RNAs in various diseases and cell types to identify such novelties (9)(10)(11)(12)(13)(14)(15)(16).…”