Abstract
The deep-sequencing of small RNAs has revealed that different numbers and proportions of miRNA variants called isomiRs are formed from single miRNA genes and that this effect is attributable mainly to imprecise cleavage by Drosha and Dicer. Factors that influence the degree of cleavage precision of Drosha and Dicer are under investigation, and their identification may improve our understanding of the mechanisms by which cells modulate the regulatory potential of miRNAs. In this study, we focused on the sequences and structural determinants of Drosha and Dicer cleavage sites, which may explain the generation of homogeneous miRNAs (in which a single isomiR strongly predominates) as well as the generation of heterogeneous miRNAs. Using deep-sequencing data for small RNAs, we demonstrate that the generation of homogeneous miRNAs requires more sequence constraints at the cleavage sites than the formation of heterogeneous miRNAs. Additionally, our results indicate that specific Drosha cleavage sites have more sequence determinants in miRNA precursors than specific cleavage sites for Dicer and that secondary structural motifs in the miRNA precursors influence the precision of Dicer cleavage. Together, we present the sequence and structural features of Drosha and Dicer cleavage sites that influence the heterogeneity of the released miRNAs.
Highlights
It is well proven that each miRNA gene gives rise to a population of heterogeneous products called isomiRs, which have variable lengths and end-sequences, rather than to a single mature miRNA [1,2,3]
We propose that nucleotide sequences at and around Drosha and Dicer cleavage sites may play an important role in determining the level of miRNA heterogeneity
We analyzed the sources of miRNA length diversity from the perspective of the miRNA precursor structure as well as the role of proteins that cooperate with Dicer in miRNA
Summary
It is well proven that each miRNA gene gives rise to a population of heterogeneous products called isomiRs, which have variable lengths and end-sequences, rather than to a single mature miRNA [1,2,3]. The question of whether the nucleotide sequence preferences at the sites of Drosha and Dicer cleavage are involved in generating either homogeneous or heterogeneous miRNAs has not yet been addressed. Our study is the first to address the issue of the nucleotide sequence contribution at Drosha and Dicer cleavage sites to the formation of the homogeneous and heterogeneous miRNAs. We analyzed the nucleotide composition at Drosha and Dicer cleavage sites with the use of publicly available small RNA deep-sequencing data. The results of our analyses expand existing knowledge regarding sequence biases observed at miRNA ends This observation is further analyzed in detail in the context of the homogeneity and heterogeneity of miRNA generated by Drosha and Dicer. Our results shed new light on the issue of the formation of the isomiRs, the abundance of which reflects the sequence preference of Drosha and Dicer cleavages
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