Cisregulation within a cluster of viral microRNAs

Abstract

MicroRNAs (miRNAs) are small regulatory RNAs involved in virtually all biological processes. Although a large number of them are co-expressed from clusters, little is known regarding the impact of this organization on the regulation of their accumulation. In this study, we set to decipher the regulatory mechanism controlling the expression of the ten clustered pre-miRNAs from Kaposi’s sarcoma associated herpesvirus (KSHV). We measured in vitro the efficiency of cleavage of each individual pre-miRNA by the Microprocessor. Strikingly, pre-miR-K1 and -K3 were the most efficiently cleaved pre-miRNAs but their mature forms accumulated at low levels, indicating that they might perform an additional function. A mutational analysis showed that they are indeed important for the optimal expression of the whole set of miRNAs. We showed that this solely relies on the presence of a canonical pre-miRNA at this localization since we could functionally replace pre-miR-K1 by a heterologous pre-miRNA. Further in vitro processing analysis suggests that the two stem-loops act in cis and that the cluster is cleaved in a sequential manner. Finally, we showed that we can exploit this feature of the cluster to inhibit the expression of the whole set of miRNAs by targeting the pre-miR-K1 with LNA-based antisense oligonucleotides.

Correction to ‘Cis regulation within a cluster of viral microRNAs’

“…Errors were introduced in equations 2 and 3’ during production of the article ( 1 ). The publisher apologises for these errors and wishes to correct the equations as shown below.…”