Abstract
Cells regulate gene expression at multiple levels leading to a balance between robustness and complexity within their proteome. One core molecular step contributing to this important balance during metazoan gene expression is RNA editing, such as the co-transcriptional recoding of RNA transcripts catalyzed by the adenosine deaminse acting on RNA (ADAR) family of enzymes. Understanding of the adenosine-to-inosine RNA editing process has been broadened considerably by the next generation sequencing (NGS) technology, which allows for in-depth demarcation of an RNA editome at nucleotide resolution. However, critical issues remain unresolved with regard to how RNA editing cooperates with other transcript-associated events to underpin regulated gene expression. Here we review the growing body of evidence, provided by recent NGS-based studies, that links RNA editing to other mechanisms of post-transcriptional RNA processing and gene expression regulation including alternative splicing, transcript stability and localization, and the biogenesis and function of microRNAs (miRNAs). We also discuss the possibility that systematic integration of NGS data may be employed to establish the rules of an “RNA editing code”, which may give us new insights into the functional consequences of RNA editing.
Highlights
RNA editing: a core constituent of the transcriptome The transcriptome is the complete set of RNA molecules in a cell, expression of which is finely and dynamically regulated to meet the cellular needs associated with a particular developmental or physiological state
RNA editing events, the majority of which are of the adenosine-to-inosine (A-to-I) type base changes, represent a core co-transcriptional process by which transcripts are covalently modified in a manner that results in an RNA sequence different from that encoded by the genomic DNA [1,2,3]
Similar analyses and studies can be extended to deciphering the impact of RNA editing on post-transcriptional attributes of the transcripts, such as alternative splicing and transcript stability
Summary
RNA editing: a core constituent of the transcriptome The transcriptome is the complete set of RNA molecules in a cell, expression of which is finely and dynamically regulated to meet the cellular needs associated with a particular developmental or physiological state. Peng et al found that A-to-G variants are less overrepresented among the editing types in the miRNA sequences, implying the existence of a nonADAR-based mechanism in this context [31] Together, these observations strengthen the connection between RNA editing and miRNA-mediated regulation of gene expression. A study by Wang et al recently illustrated the functional relevance of this regional RNA editing, showing that this type of sequence alteration leads to interference of the target signals and the binding of miR-30b-3p and miR-573 to the transcript of ARHGAP26 [52] Both highthroughput and gene-specific studies imply that RNA editing may acquire functionality by conferring variable susceptibility to miRNA-mediated repression. Further revealing the role of ADAR1 in transcription may come from global techniques that measure the synthesis rates of nascent transcripts, such as the metabolic labeling (4sU-Seq) [57] and global nuclear run-on (GRO-Seq) [58] methods
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