Differential Sensitivity of Target Genes to Translational Repression by miR-17~92

Abstract

MicroRNAs (miRNAs) are thought to exert their functions by modulating the expression of hundreds of target genes and each to a small degree, but it remains unclear how small changes in hundreds of target genes are translated into the specific function of a miRNA. Here, we conducted an integrated analysis of transcriptome and translatome of primary B cells from mutant mice expressing miR-17~92 at three different levels to address this issue. We found that target genes exhibit differential sensitivity to miRNA suppression and that only a small fraction of target genes are actually suppressed by a given concentration of miRNA under physiological conditions. Transgenic expression and deletion of the same miRNA gene regulate largely distinct sets of target genes. miR-17~92 controls target gene expression mainly through translational repression and 5’UTR plays an important role in regulating target gene sensitivity to miRNA suppression. These findings provide molecular insights into a model in which miRNAs exert their specific functions through a small number of key target genes.

Translational control of ERK signaling through miRNA/4EHP-directed silencing

“…The relative contributions of translational repression and mRNA decay in miRNA-mediated silencing are in dispute. Several large-scale studies reported that mammalian miRNAs predominantly act by decreasing target mRNA levels ( Baek et al, 2008 ; Eichhorn et al, 2014 ; Guo et al, 2010 ), while others showed that miRNAs affect the expression of target genes by translation inhibition ( Jin et al, 2017 ; Selbach et al, 2008 ; Yang et al, 2009 ). It was convincingly demonstrated in in vitro and in vivo studies that translational repression precedes target mRNA decay ( Bazzini et al, 2012 ; Béthune et al, 2012 ; Djuranovic et al, 2012 ; Fabian et al, 2009 ; Mathonnet et al, 2007 ).…”

Decreased production of class-switched antibodies in neonatal B cells is associated with increased expression of miR-181b

“…Whereas prior studies employed ectopic expression of AID in in vitro cultured B cells, we analyzed Aicda expression directly ex vivo comparing either adult and neonatal states or miR-181a/b-deficient and sufficient scenarios. Interestingly, a recent study on miR-17~92 targets during early B cell development showed that opposing changes in miRNA expression levels resulted in the identification of fundamentally distinct groups of miRNA targets [ 74 ].…”

MicroRNA-mediated Regulation of the Development and Functions of Follicular Helper T cells

“…Many research groups are currently pursuing answers to this abstruse question, including Xiao and colleagues ( 54 55 ). Recently, this group executed an elegant systemic transcriptome and translatome analysis of miR-17–92-deficient or overexpressed primary B cells ( 56 ). Although the conclusions of this study were not able to provide clear answers to this question, they nevertheless provided important insights on this issue.…”