Antagonistic role of hnRNP A1 and KSRP in the regulation of let-7a biogenesis

let-7a, a miRNA involved in differentiation, was known to be regulated by Lin-28. Now work reveals another factor that could control let-7a levels in vivo : hnRNP A1 binds to unprocessed pri-let-7a and inhibits its processing by Drosha. The inhibitory effect of hnRNP A1 is further shown to occur via antagonizing the binding of KSRP to pri-let-7a, which is known to promote biogenesis. The pluripotency-promoting proteins Lin28a and Lin28b act as post-transcriptional repressors of let-7 miRNA biogenesis in undifferentiated embryonic stem cells. The levels of mature let-7a differ substantially in cells lacking Lin28 expression, indicating the existence of additional mechanism(s) of post-transcriptional regulation. Here, we present evidence supporting a role for heteronuclear ribonucleoprotein A1 (hnRNP A1) as a negative regulator of let-7a. HnRNP A1 binds the conserved terminal loop of pri-let-7a-1 and inhibits its processing by Drosha. Levels of mature let-7a negatively correlate with hnRNP A1 levels in somatic cell lines. Furthermore, hnRNP A1 depletion increased pri-let-7a-1 processing by cell extracts, whereas its ectopic expression decreased let-7a production in vivo . Finally, hnRNP A1 binding to let-7a interferes with the binding of KSRP, which is known to promote let-7a biogenesis. We propose that hnRNP A1 and KSRP have antagonistic roles in the post-transcriptional regulation of let-7a expression.