Article | Published:

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

Nature Structural & Molecular Biology volume 21, pages 585590 (2014) | Download Citation

Abstract

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.

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Acknowledgements

We thank members of the Chang laboratory, and P. Sharp (Massachusetts Institute of Technology) and A. Giraldez (Yale) for discussion, and for sharing unpublished data. We thank R. Blelloch (University of California, San Francisco) and A. Bradley (Wellcome Trust Sanger Institute) for sharing DGCR8 WT and KO mESCs, and cMyc KO mESCs respectively. G.X.Y.Z. was supported by the Leukemia and Lymphoma Society (grant 5549-13 to G.X.Y.Z.) and a Dean's Fellowship from Stanford University. The study was supported by the US National Institutes of Health (grant R01-CA118750 to H.Y.C.) and California Institute for Regenerative Medicine (grant RB4-05763 to H.Y.C.). H.Y.C. is supported as an Early Career Scientist of the Howard Hughes Medical Institute.

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Affiliations

  1. Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.

    • Grace X Y Zheng
    • , Brian T Do
    • , Dan E Webster
    • , Paul A Khavari
    •  & Howard Y Chang
  2. Howard Hughes Medical Institute, Stanford, California, USA.

    • Howard Y Chang

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Contributions

G.X.Y.Z. and H.Y.C. initiated the project. G.X.Y.Z. and H.Y.C. designed the experiments. G.X.Y.Z. performed the experiments and the computational analysis. B.T.D., D.E.W. and P.A.K. designed and implemented bioinformatics and microarray screens. The manuscript was prepared by G.X.Y.Z. and H.Y.C. with input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Howard Y Chang.

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DOI

https://doi.org/10.1038/nsmb.2842

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