Nucleotide Modification Alters MicroRNA-Dependent Silencing of MicroRNA Switches.

Mol Ther Nucleic Acids

Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA. Electronic address:

Published: March 2019

AI Article Synopsis

  • mRNA therapeutics show potential for treating diseases, but selective expression challenges limit their clinical use.
  • Researchers have explored the impact of nucleotide modifications like pseudouridine and 5-methylcytidine on microRNA (miRNA) regulation and found they can reduce the control of miRNA switches.
  • The study reveals that these modifications are specific to the miRNA switches and that certain placements, like in the 5' UTR, can negate the effects of these nucleotide changes on miRNA silencing.

Article Abstract

mRNA therapeutics hold great promise for the treatment of human diseases. While incorporating naturally occurring modified nucleotides during synthesis has greatly increased their potency and safety, challenges in selective expression have hindered clinical applications. MicroRNA (miRNA)-regulated in vitro-transcribed mRNAs, called miRNA switches, have been used to control the expression of exogenous mRNA in a cell-selective manner. However, the effect of nucleotide modifications on miRNA-dependent silencing has not been examined. Here we show that the incorporation of pseudouridine, N1-methylpseudourdine, or pseudouridine and 5-methylcytidine, which increases translation, tends to decrease the regulation of miRNA switches. Moreover, pseudouridine and 5-methylcytidine modification enables one miRNA target site at the 3' UTR to be as effective as four target sites. We also demonstrate that the effects of pseudouridine, pseudouridine and 5-methylcytidine, and N1-methylpseudourdine modification are miRNA switch specific and do not correlate with the proportion of modified nucleotides in the miRNA target site. Furthermore, modified miRNA switches containing seed-complementary target sites are poorly regulated by miRNA. We also show that placing the miRNA target site in the 5' UTR of the miRNA switch abolishes the effect of nucleotide modification on miRNA-dependent silencing. This work provides insights into the influence of nucleotide modifications on miRNA-dependent silencing and informs the design of optimal miRNA switches.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350232PMC
http://dx.doi.org/10.1016/j.omtn.2018.12.007DOI Listing

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