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

F1000Res. 2021 Mar 5;10:182. doi: 10.12688/f1000research.28510.2. eCollection 2021.

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: VtRNAs promoters are enriched in transcription factors related to viral infection. VtRNA2-1 is likely the most independently regulated homologue. VtRNA1-1 has the most accessible chromatin, followed by vtRNA1-2, vtRNA2-1 and vtRNA1-3. 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 chromatin status 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.

Keywords: DNA methylation; TCGA; cancer; chromatin accessibility; mir-886; nc886; vault RNA; vtRNA1-1; vtRNA1-2; vtRNA1-3; vtRNA2-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biology
  • Chromatin* / genetics
  • DNA Methylation
  • Humans
  • Neoplasms* / genetics
  • RNA / metabolism

Substances

  • Chromatin
  • RNA

Grant support

This work was supported by Comision Academica de Posgrado, UDELAR (Student Fellowship RF 2020); Comisión Sectorial de Investigación Científica (CSIC, UDELAR) (Research Grant MAD I+D 2016 #487); Agencia Nacional de Investigación e Innovación (ANII) (Student Fellowship RF 2016-2019); and Programa para el Desarrollo de las Ciencias Basicas (PEDECIBA, MEC).