Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA
Shashank Sathe
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA
Emily C. Wheeler
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA
Gene W. Yeo
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA; Corresponding author
Summary: 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.
