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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


Primary accessions

Gene Expression Omnibus


  1. 1.

    & Genome regulation by long noncoding RNAs. Annu. Rev. Biochem. 81, 145–166 (2012).

  2. 2.

    & Long noncoding RNAs: cellular address codes in development and disease. Cell 152, 1298–1307 (2013).

  3. 3.

    MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).

  4. 4.

    , & miRcode: a map of putative microRNA target sites in the long non-coding transcriptome. Bioinformatics 28, 2062–2063 (2012).

  5. 5.

    et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147, 358–369 (2011).

  6. 6.

    et al. microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene 30, 4750–4756 (2011).

  7. 7.

    , & The multilayered complexity of ceRNA crosstalk and competition. Nature 505, 344–352 (2014).

  8. 8.

    , , & RNA sequence analysis defines Dicer's role in mouse embryonic stem cells. Proc. Natl. Acad. Sci. USA 104, 18097–18102 (2007).

  9. 9.

    et al. A latent pro-survival function for the mir-290–295 cluster in mouse embryonic stem cells. PLoS Genet. 7, e1002054 (2011).

  10. 10.

    et al. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477, 295–300 (2011).

  11. 11.

    et al. Ab initio reconstruction of cell type–specific transcriptomes in mouse reveals the conserved multi-exonic structure of lincRNAs. Nat. Biotechnol. 28, 503–510 (2010).

  12. 12.

    , & TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009).

  13. 13.

    et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28, 511–515 (2010).

  14. 14.

    , & Evolution and functions of long noncoding RNAs. Cell 136, 629–641 (2009).

  15. 15.

    & lincRNAs: genomics, evolution, and mechanisms. Cell 154, 26–46 (2013).

  16. 16.

    et al. Genome-wide identification of Ago2 binding sites from mouse embryonic stem cells with and without mature microRNAs. Nat. Struct. Mol. Biol. 18, 237–244 (2011).

  17. 17.

    et al. Metabolic labeling of RNA uncovers principles of RNA production and degradation dynamics in mammalian cells. Nat. Biotechnol. 29, 436–442 (2011).

  18. 18.

    et al. Database for mRNA half-life of 19 977 genes obtained by DNA microarray analysis of pluripotent and differentiating mouse embryonic stem cells. DNA Res. 16, 45–58 (2009).

  19. 19.

    , & Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature 463, 621–626 (2010).

  20. 20.

    et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).

  21. 21.

    et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 25, 1915–1927 (2011).

  22. 22.

    et al. GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res. 22, 1760–1774 (2012).

  23. 23.

    , , , & A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. Genes Dev. 7, 671–682 (1993).

  24. 24.

    et al. c-Myc regulates transcriptional pause release. Cell 141, 432–445 (2010).

  25. 25.

    , , , & Promoter directionality is controlled by U1 snRNP and polyadenylation signals. Nature 499, 360–363 (2013).

  26. 26.

    et al. Transcriptome analysis by strand-specific sequencing of complementary DNA. Nucleic Acids Res. 37, e123 (2009).

  27. 27.

    , & Using ChIP-seq technology to generate high-resolution profiles of histone modifications. Methods Mol. Biol. 791, 265–286 (2011).

  28. 28.

    et al. The UCSC Table Browser data retrieval tool. Nucleic Acids Res. 32, D493–D496 (2004).

  29. 29.

    & Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010).

  30. 30.

    , , & Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).

  31. 31.

    et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).

  32. 32.

    , & Transcriptional regulatory networks in embryonic stem cells. Cold Spring Harb. Symp. Quant. Biol. 73, 203–209 (2008).

  33. 33.

    et al. Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells. Proc. Natl. Acad. Sci. USA 110, 2876–2881 (2013).

  34. 34.

    et al. Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition. Genome Res. 24, 751–760 (2014).

Download references


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.

Author information


  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


  1. Search for Grace X Y Zheng in:

  2. Search for Brian T Do in:

  3. Search for Dan E Webster in:

  4. Search for Paul A Khavari in:

  5. Search for Howard Y Chang in:


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.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–5 and Supplementary Table 1

About this article

Publication history





Further reading