Journal Article

The biochemical basis of microRNA targeting efficacy

Shi, Charlie Y., Pham, Thy M., Kelley, Gina M., Bartel, David P., Lin, Kathy S., Bisaria, Namita, McGeary, Sean E.

2019

Overview

MicroRNAs (miRNAs) regulate most human messenger RNAs and play essential roles in diverse developmental and physiological processes. Correctly predicting the function of each miRNA requires a better understanding of miRNA targeting efficacy. McGeary et al. measured binding affinities between six miRNAs and synthetic targets, built a biochemical model of miRNA-mediated repression, and expanded it to all miRNAs using a convolutional neural network. This approach offers insights into miRNA targeting and enables more accurate prediction of intracellular miRNA repression efficacy than previous algorithms. Science , this issue p. eaav1741 Millions of affinity measurements reveal microRNA-specific preferences and other insights that advance microRNA target prediction. MicroRNAs (miRNAs) act within Argonaute proteins to guide repression of messenger RNA targets. Although various approaches have provided insight into target recognition, the sparsity of miRNA-target affinity measurements has limited understanding and prediction of targeting efficacy. Here, we adapted RNA bind-n-seq to enable measurement of relative binding affinities between Argonaute-miRNA complexes and all sequences ≤12 nucleotides in length. This approach revealed noncanonical target sites specific to each miRNA, miRNA-specific differences in canonical target-site affinities, and a 100-fold impact of dinucleotides flanking each site. These data enabled construction of a biochemical model of miRNA-mediated repression, which was extended to all miRNA sequences using a convolutional neural network. This model substantially improved prediction of cellular repression, thereby providing a biochemical basis for quantitatively integrating miRNAs into gene-regulatory networks.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Affinity / Algorithms / Argonaute Proteins - chemistry / Artificial neural networks / Base Sequence / Binding sites / Biochemistry / Correlation / Destabilization / Effectiveness / Gene Expression Regulation / Gene sequencing / HEK293 Cells / Humans / MicroRNAs / MicroRNAs - chemistry / miRNA / Networks / Neural networks / Nucleotides / Physiological effects / Physiology / Protein Binding / Proteins / RESEARCH ARTICLE SUMMARY / Ribonucleic acid / RNA / Sequence Analysis, RNA - methods / Target recognition / Thermodynamic models