De Novo A-to-I RNA Editing Discovery in lncRNA

SIMPLE SUMMARY: Long non-coding RNAs are emerging as key regulators of gene expression at both transcriptional and translational levels, and their alterations (in expression or sequence) are linked to tumorigenesis and tumor progression. RNA editing has the unique ability to change the RNA sequence without altering the integrity or sequence of genomic DNA, with adenosine to inosine (A-to-I) RNA editing being the most common event in humans. With the ability to change the genetic information after transcription, RNA editing is an essential player in the transcriptome and proteome enrichment; however, when deregulated, it can contribute to cell transformation. In this article, we performed the first deep de novo editing survey in lncRNA, demonstrating that RNA editing is a pervasive phenomenon involving lncRNAs important in the brain and brain cancer. Our study will open a new field of research in which the interplay between lncRNA and RNA editing can add novel insights into cancer. ABSTRACT: Background: Adenosine to inosine (A-to-I) RNA editing is the most frequent editing event in humans. It converts adenosine to inosine in double-stranded RNA regions (in coding and non-coding RNAs) through the action of the adenosine deaminase acting on RNA (ADAR) enzymes. Long non-coding RNAs, particularly abundant in the brain, account for a large fraction of the human transcriptome, and their important regulatory role is becoming progressively evident in both normal and transformed cells. Results: Herein, we present a bioinformatic analysis to generate a comprehensive inosinome picture in long non-coding RNAs (lncRNAs), using an ad hoc index and searching for de novo editing events in the normal brain cortex as well as in glioblastoma, a highly aggressive human brain cancer. We discovered >10,000 new sites and 335 novel lncRNAs that undergo editing, never reported before. We found a generalized downregulation of editing at multiple lncRNA sites in glioblastoma samples when compared to the normal brain cortex. Conclusion: Overall, our study discloses a novel layer of complexity that controls lncRNAs in the brain and brain cancer.