Pan-cancer chromatin analysis of the human vtRNA genes uncovers their association with cancer biology.

Published on Mar 5, 2021in F1000Research
· DOI :10.12688/F1000RESEARCH.28510.2
Rafael Sebastián Fort6
Estimated H-index: 6
(University of the Republic),
María Ana Duhagon12
Estimated H-index: 12
(University of the Republic)
Sources
Abstract
Background: The vault RNAs (vtRNAs) are a class of 84-141-nt eukaryotic non-coding RNAs transcribed by RNA polymerase III, associated to the ribonucleoprotein complex known as vault particle. Of the four human vtRNA genes, vtRNA1-1, vtRNA1-2 and vtRNA1-3, clustered at locus 1, are integral components of the vault particle, while vtRNA2-1 is a more divergent homologue located in a second locus. Gene expression studies of vtRNAs in large cohorts have been hindered by their unsuccessful sequencing using conventional transcriptomic approaches. Methods: VtRNA expression in The Cancer Genome Atlas (TCGA) Pan-Cancer cohort was estimated using the genome-wide DNA methylation and chromatin accessibility data (ATAC-seq) of their genes as surrogate variables. The association between vtRNA expression and patient clinical outcome, immune subtypes and transcriptionally co-regulated gene programs was analyzed in the dataset. Results: VtRNA1-1 has the most accessible chromatin, followed by vtRNA1-2, vtRNA2-1 and vtRNA1-3. Although the vtRNAs are co-regulated by transcription factors related to viral infection, vtRNA2-1 is the most independently regulated homologue. VtRNA1-1 and vtRNA1-3 chromatin status does not significantly change in cancer tissues. Meanwhile, vtRNA2-1 and vtRNA1-2 expression is widely deregulated in neoplastic tissues and its alteration is compatible with a broad oncogenic role for vtRNA1-2, and both tumor suppressor and oncogenic functions for vtRNA2-1. Yet, vtRNA1-1, vtRNA1-2 and vtRNA2-1 promoter DNA methylation predicts a shorter patient overall survival cancer-wide. In addition, gene ontology analyses of vtRNAs co-regulated genes identify a chromosome regulatory domain, epithelial differentiation, immune and thyroid cancer gene sets for specific vtRNAs. Furthermore, vtRNA expression patterns are associated with cancer immune subtypes and vtRNA1-2 expression is positively associated with cell proliferation and wound healing. Conclusions: Our study presents the landscape of vtRNA expression cancer-wide, identifying co-regulated gene networks and ontological pathways associated with the different vtRNA genes that may account for their diverse roles in cancer.
References129
Newest
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#1Ming-Chin Yu (CGU: Chang Gung University)H-Index: 24
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Abstract Background Vault RNA 2-1 (VTRNA2-1, also called nc886) is a 108-nucleotide noncoding transcript that is epigenetically controlled via 18 CpG dinucleotide modifications of its promoter, and can exert either tumor suppressor or oncogenic functions depending on cell types of cancers. In hepatocellular carcinoma (HCC), the role of VTRNA2-1 in prognosis of patients remains unexplored. Here, we analysed the methylation status of the VTRNA2-1 promoter and its correlation with clinical paramete...
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