Lineage-Specific Transcriptional Regulation of DICER by MITF in Melanocytes

SummaryDICER is a central regulator of microRNA maturation. However, little is known about mechanisms regulating its expression in development or disease. While profiling miRNA expression in differentiating melanocytes, two populations were observed: some upregulated at the pre-miRNA stage, and others upregulated as mature miRNAs (with stable pre-miRNA levels). Conversion of pre-miRNAs to fully processed miRNAs appeared to be dependent upon stimulation of DICER expression—an event found to occur via direct transcriptional targeting of DICER by the melanocyte master transcriptional regulator MITF. MITF binds and activates a conserved regulatory element upstream of DICER's transcriptional start site upon melanocyte differentiation. Targeted KO of DICER is lethal to melanocytes, at least partly via DICER-dependent processing of the pre-miRNA-17∼92 cluster thus targeting BIM, a known proapoptotic regulator of melanocyte survival. These observations highlight a central mechanism underlying lineage-specific miRNA regulation which could exist for other cell types during development.

Graphical AbstractFigure optionsDownload high-quality image (219 K)Download as PowerPoint slideHighlights
► Stimulation of DICER expression required to achieve fully mature miRNAs in melanocytes
► MITF directly upregulates DICER transcription upon melanocyte differentiation
► DICER targeted knockout is lethal to melanocytes in vivo and in vitro
► DICER processing of miR17∼92 regulates melanocytes survival via targeting BIM