Integrative transcriptome analysis suggest processing of a subset of long non-coding RNAs to small RNAs

Background: The availability of sequencing technology has enabled understanding of transcriptomes through genome-wide approaches including RNA-sequencing. Contrary to the previous assumption that large tracts of the eukaryotic genomes are not transcriptionally active, recent evidence from transcriptome sequencing approaches have revealed pervasive transcription in many genomes of higher eukaryotes. Many of these loci encode transcripts that have no obvious protein-coding potential and are designated as non-coding RNA (ncRNA). Non-coding RNAs are classified empirically as small and long non-coding RNAs based on the size of the functional RNAs. Each of these classes is further classified into functional subclasses. Although microRNAs (miRNA), one of the major subclass of ncRNAs, have been extensively studied for their roles in regulation of gene expression and involvement in a large number of patho-physiological processes, the functions of a large proportion of long non-coding RNAs (lncRNA) still remains elusive. We hypothesized that some lncRNAs could potentially be processed to small RNA and thus could have a dual regulatory output. Results: Integration of large-scale independent experimental datasets in public domain revealed that certain well studied lncRNAs harbor small RNA clusters. Expression analysis of the small RNA clusters in different tissue and cell types reveal that they are differentially regulated suggesting a regulated biogenesis mechanism. Conclusions: Our analysis suggests existence of a potentially novel pathway for lncRNA processing into small RNAs. Expression analysis, further suggests that this pathway is regulated. We argue that this evidence supports our hypothesis, though limitations of the datasets and analysis cannot completely rule out alternate possibilities. Further in-depth experimental verification of the observation could potentially reveal a novel pathway for biogenesis. Reviewers: This article was reviewed by Dr Rory Johnson (nominated by Fyodor Kondrashov), Dr Raya Khanin (nominated by Dr Yuriy Gusev) and Prof Neil Smalheiser. For full reviews, please go to the Reviewer's comment section.