Instituto de Agrobiotecnología del Litoral, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Santa Fe, Argentina.
Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral (UNL), Santa Fe, Argentina.
PLoS Genet. 2023 Aug 28;19(8):e1010721. doi: 10.1371/journal.pgen.1010721. eCollection 2023 Aug.
The conserved transcription factor Myc regulates cell growth, proliferation and apoptosis, and its deregulation has been associated with human pathologies. Although specific miRNAs have been identified as fundamental components of the Myc tumorigenic program, how Myc regulates miRNA biogenesis remains controversial. Here we showed that Myc functions as an important regulator of miRNA biogenesis in Drosophila by influencing both miRNA gene expression and processing. Through the analysis of ChIP-Seq datasets, we discovered that nearly 56% of Drosophila miRNA genes show dMyc binding, exhibiting either the canonical or non-canonical E-box sequences within the peak region. Consistently, reduction of dMyc levels resulted in widespread downregulation of miRNAs gene expression. dMyc also modulates miRNA processing and activity by controlling Drosha and AGO1 levels through direct transcriptional regulation. By using in vivo miRNA activity sensors we demonstrated that dMyc promotes miRNA-mediated silencing in different tissues, including the wing primordium and the fat body. We also showed that dMyc-dependent expression of miR-305 in the fat body modulates Dmp53 levels depending on nutrient availability, having a profound impact on the ability of the organism to respond to nutrient stress. Indeed, dMyc depletion in the fat body resulted in extended survival to nutrient deprivation which was reverted by expression of either miR-305 or a dominant negative version of Dmp53. Our study reveals a previously unrecognized function of dMyc as an important regulator of miRNA biogenesis and suggests that Myc-dependent expression of specific miRNAs may have important tissue-specific functions.
保守转录因子 Myc 调节细胞生长、增殖和凋亡，其失调与人类病理有关。虽然已经确定了特定的 miRNA 是 Myc 致癌程序的基本组成部分，但 Myc 如何调节 miRNA 的生物发生仍存在争议。在这里，我们通过影响 miRNA 基因的表达和加工，表明 Myc 是果蝇 miRNA 生物发生的重要调节因子。通过分析 ChIP-Seq 数据集，我们发现近 56%的果蝇 miRNA 基因显示出 dMyc 结合，在峰区显示出典型或非典型的 E-box 序列。一致地，dMyc 水平的降低导致 miRNA 基因表达的广泛下调。dMyc 还通过直接转录调节来控制 Drosha 和 AGO1 水平来调节 miRNA 的加工和活性。通过使用体内 miRNA 活性传感器，我们证明 dMyc 促进不同组织中的 miRNA 介导的沉默，包括翅原基和脂肪体。我们还表明，脂肪体中 dMyc 依赖性表达的 miR-305 调节 Dmp53 水平，这取决于营养物质的可用性，对生物体应对营养压力的能力有深远的影响。事实上，脂肪体中 dMyc 的耗竭导致对营养剥夺的存活时间延长，而通过表达 miR-305 或 Dmp53 的显性负版本可以恢复这种延长。我们的研究揭示了 dMyc 作为 miRNA 生物发生的重要调节因子的先前未被认识的功能，并表明特定 miRNA 的 Myc 依赖性表达可能具有重要的组织特异性功能。
