Research Article: Genome-wide identification and analysis of A-to-I RNA editing events in bovine by transcriptome sequencing

Date Published: February 22, 2018

Publisher: Public Library of Science

Author(s): Mohammad Reza Bakhtiarizadeh, Abdolreza Salehi, Rocío Melissa Rivera, Yun Zheng.

http://doi.org/10.1371/journal.pone.0193316

Abstract

RNA editing increases the diversity of the transcriptome and proteome. Adenosine-to-inosine (A-to-I) editing is the predominant type of RNA editing in mammals and it is catalyzed by the adenosine deaminases acting on RNA (ADARs) family. Here, we used a largescale computational analysis of transcriptomic data from brain, heart, colon, lung, spleen, kidney, testes, skeletal muscle and liver, from three adult animals in order to identify RNA editing sites in bovine. We developed a computational pipeline and used a rigorous strategy to identify novel editing sites from RNA-Seq data in the absence of corresponding DNA sequence information. Our methods take into account sequencing errors, mapping bias, as well as biological replication to reduce the probability of obtaining a false-positive result. We conducted a detailed characterization of sequence and structural features related to novel candidate sites and found 1,600 novel canonical A-to-I editing sites in the nine bovine tissues analyzed. Results show that these sites 1) occur frequently in clusters and short interspersed nuclear elements (SINE) repeats, 2) have a preference for guanines depletion/enrichment in the flanking 5′/3′ nucleotide, 3) occur less often in coding sequences than other regions of the genome, and 4) have low evolutionary conservation. Further, we found that a positive correlation exists between expression of ADAR family members and tissue-specific RNA editing. Most of the genes with predicted A-to-I editing in each tissue were significantly enriched in biological terms relevant to the function of the corresponding tissue. Lastly, the results highlight the importance of the RNA editome in nervous system regulation. The present study extends the list of RNA editing sites in bovine and provides pipelines that may be used to investigate the editome in other organisms.

Partial Text

The biology of the mammalian transcriptome is far more complex than once thought. Previous studies have shed light on the dynamic nature of the mammalian transcriptome, where different molecular processes interact to fine-tune gene expression [1]. For instance, large-scale projects based on high throughput cDNA sequencing technology (RNA-Seq), such as ENCODE [2] and GENCODE [3] have clearly shown that RNA transcripts undergo a host of diverse processing mechanisms. One such mechanism is RNA editing, which is defined as any post-transcriptional or co-transcriptional mechanism that alters the nucleotide composition of a transcript. Therefore, this phenomenon leads to differences between the final transcript sequence and the DNA region it was transcribed from [4]. Since its discovery in 1986 in trypanosomes [5], RNA editing has been reported to occur in a broad range of species ranging from bacteria [6] to mammals [7, 8]. As inosines are read as guanosine by the translation and splicing machineries [4, 9], RNA editing can influence alternative splicing [10], recoding of open reading frames [4] and can affect miRNA-regulated post-transcriptional gene silencing [11]. RNA editing plays vital roles in the development and maintenance of the metazoan nervous system [12], marking RNAs for degradation, modulating nuclear retention of RNAs [9] and when deregulated, this mechanism is associated with various diseases [13] and cancers [14].

RNA editing increases the proteome and transcriptome diversity in eukaryotic genomes [8, 12, 46, 47]. While in human [8, 12, 14] and mouse [16], the A-to-I RNA editome is well characterized, in bovine only two studies have reported on this type of RNA posttranscriptional modification [26, 27]. Hence, the comprehensive identification of the bovine editome is needed for the understanding of post-transcriptional gene regulation in this agriculturally important species.

Here, we used a large number of RNA-Seq samples along with a computational method with multiple filters and stringent thresholds to facilitate unbiased detection of bona fide RNA editing sites in the bovine genome in the absence of corresponding DNA information. The present study extends the list of RNA editing sites in bovine and provides pipelines that may be used to investigate the editome in other organisms.

 

Source:

http://doi.org/10.1371/journal.pone.0193316

 

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