Department of Dermatology, Cutaneous Biology Research Center, Mass. General Hospital, Harvard Medical School, MA 02115, USA.
Cell. 2010 Jun 11;141(6):994-1005. doi: 10.1016/j.cell.2010.05.004.
DICER 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 approximately 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.
DICER 是 microRNA 成熟的核心调控因子。然而，关于其在发育或疾病中表达的调控机制知之甚少。在研究分化的黑素细胞中的 miRNA 表达谱时，观察到两种群体：一些在 pre-miRNA 阶段上调，另一些则作为成熟 miRNA（具有稳定的 pre-miRNA 水平）上调。pre-miRNA 向完全加工的 miRNA 的转化似乎依赖于 DICER 表达的刺激——这一事件通过 MITF 对 DICER 的直接转录靶向而发生，MITF 是黑素细胞主转录调节剂。在黑素细胞分化过程中，MITF 结合并激活 DICER 转录起始位点上游的保守调控元件。DICER 的靶向 KO 对黑素细胞是致命的，至少部分是通过 DICER 依赖的 pre-miRNA-17 大约 92 簇的加工，从而靶向 BIM，BIM 是已知的黑素细胞存活的促凋亡调节剂。这些观察结果突出了发育过程中其他细胞类型中存在的特定谱系 miRNA 调控的核心机制。
