Dicer-microRNA-Myc circuit promotes transcription of hundreds of long noncoding RNAs

• Published in: Nature structural & molecular biology Vol. 21; no. 7; pp. 585 - 590
• Main Authors: Zheng, Grace X Y, Do, Brian T, Webster, Dan E, Khavari, Paul A, Chang, Howard Y
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2014; Nature Publishing Group
• Subjects: 38/91; 45/15; 45/91; 631/114; Animals; Biochemistry; Biological Microscopy; Cellular biology; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; DEAD-box RNA Helicases - physiology; Down-Regulation; Gene expression; Gene Knockout Techniques; Life Sciences; Membrane Biology; Mice; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; MicroRNAs - physiology; Noncoding DNA; Protein Structure; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Proto-Oncogene Proteins c-myc - physiology; Ribonuclease III - genetics; Ribonuclease III - metabolism; Ribonuclease III - physiology; RNA, Long Noncoding - genetics; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; RNA-Binding Proteins - physiology; Stem cells; Transcription factors; Transcription, Genetic; Transcriptome; United States
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.2842

Chang and colleagues report the involvement of a Dicer-microRNA-cMyc signaling axis in the transcriptional regulation of a large set of long noncoding RNAs (lncRNAs). These lncRNAs are specifically dependent on cMyc, as compared to divergently transcribed protein-coding genes. Long noncoding RNAs (lncRNAs) are important regulators of cell fate, yet little is known about mechanisms controlling lncRNA expression. Here we show that transcription is quantitatively different for lncRNAs and mRNAs—as revealed by deficiency of Dicer (Dcr), a key RNase that generates microRNAs (miRNAs). Dcr loss in mouse embryonic stem cells led unexpectedly to decreased levels of hundreds of lncRNAs. The canonical Dgcr8-Dcr-miRNA pathway is required for robust lncRNA transcriptional initiation and elongation. Computational and genetic epistasis analyses demonstrated that Dcr activation of the oncogenic transcription factor cMyc is partly responsible for lncRNA expression. A quantitative metric of mRNA-lncRNA decoupling revealed that Dcr and cMyc differentially regulate lncRNAs versus mRNAs in diverse cell types and in vivo . Thus, numerous lncRNAs may be modulated as a class in development and disease, notably where Dcr and cMyc act.