Non-microRNA binding competitively inhibits LIN28 regulation

RNA binding protein (RBP) expression is finite. For RBPs that are vastly outnumbered by their potential target sites, a simple competition for binding can set the magnitude of post-transcriptional control. Here, we show that LIN28, best known for its direct regulation of let-7 miRNA biogenesis, is also indirectly regulated by its widespread binding of non-miRNA transcripts. Approximately 99% of LIN28 binding sites are found on non-miRNA transcripts, like protein coding and ribosomal RNAs. These sites are bound specifically and strongly, but they do not appear to mediate direct post-transcriptional regulation. Instead, non-miRNA sites act to sequester LIN28 protein and effectively change its functional availability, thus impeding the regulation of let-7 in cells. Together, these data show that the binding properties of the transcriptome broadly influence the ability of an RBP to mediate changes in RNA metabolism and gene expression. [Display omitted] •LIN28 directly and indirectly regulates miRNA activity•Most LIN28 binding sites are found on non-miRNAs•Non-miRNAs and miRNAs are bound with comparable affinity•Non-miRNA binding sites sequester and inhibit LIN28 activity Tan et al. show that the majority of LIN28 binding sites are found on non-miRNA transcripts like coding and ribosomal RNA. Binding to non-miRNA sites sequesters LIN28 protein and competitively inhibits the regulation of miRNAs. Non-miRNA sites can thus modulate the strength of cellular miRNA activity in cells.