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Nature Genetics
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Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells

Nature Geneticsvolume 42, pages1113–1117 (2010)Cite this article

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Abstract

The conversion of lineage-committed cells to induced pluripotent stem cells (iPSCs) by reprogramming is accompanied by a global remodeling of the epigenome1,2,3,4,5, resulting in altered patterns of gene expression2,6,7,8,9. Here we characterize the transcriptional reorganization of large intergenic non-coding RNAs (lincRNAs)10,11 that occurs upon derivation of human iPSCs and identify numerous lincRNAs whose expression is linked to pluripotency. Among these, we defined ten lincRNAs whose expression was elevated in iPSCs compared with embryonic stem cells, suggesting that their activation may promote the emergence of iPSCs. Supporting this, our results indicate that these lincRNAs are direct targets of key pluripotency transcription factors. Using loss-of-function and gain-of-function approaches, we found that one such lincRNA (lincRNA-RoR) modulates reprogramming, thus providing a first demonstration for critical functions of lincRNAs in the derivation of pluripotent stem cells.

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Figure 1: Direct reprogramming of fibroblasts converts both protein-coding genes and lincRNA expression to a pluripotent cell-specific profile.
Figure 2: Several lincRNAs show enriched expression in iPSCs compared with ESCs.
Figure 3: Transcriptional regulation of iPSC-enriched lincRNAs.
Figure 4: LincRNA-RoR expression modulates reprogramming.

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Gene Expression Omnibus

Change history

  • 03 December 2010

    In the version of this article initially published, the corresponding author designation was incomplete. The corresponding authors should be George Q. Daley and John L. Rinn. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank H. Huo and A. DeVine for technical assistance; S. Ratanasirintrawoot and E. McLoughlin for reagents; and M.W. Lensch for teratoma interpretation. J.L.R. is a Damon Runyon-Rachleff, Searle, Smith Family Foundation and Richard Merkin Foundation Scholar. S.L. was supported by a Human Frontier Science Program Organization long-term fellowship. Y.-H.L. is supported by the Agency of Science, Technology and Research International Fellowship and the A*Star Institute of Medical Biology, Singapore. G.Q.D. is an investigator of the Howard Hughes Medical Institute. Research was funded by grants from the US National Institutes of Health (NIH) to G.Q.D. (1 RC2-HL102815) and J.L.R. (1DP2OD00667-01).

Author information

Author notes

  1. In Hyun Park

    Present address: Present address: Yale Stem Cell Center, Department of genetics, Yale School of Medicine, New Haven, Connecticut, USA.,

Authors and Affiliations

  1. Division of Pediatric Hematology and Oncology, Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, Massachusetts, USA

    Sabine Loewer, Yuin-Han Loh, In Hyun Park, Matthew Curran, Tamer Onder, Suneet Agarwal, Philip D Manos, Sumon Datta, Thorsten M Schlaeger & George Q Daley

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Sabine Loewer, Yuin-Han Loh, In Hyun Park, Tamer Onder, Suneet Agarwal & George Q Daley

  3. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA

    Sabine Loewer, Yuin-Han Loh, In Hyun Park, Matthew Curran, Tamer Onder, Suneet Agarwal, Philip D Manos, Sumon Datta, Thorsten M Schlaeger & George Q Daley

  4. Stem Cell Program, Children's Hospital Boston, Boston, Massachusetts, USA

    Sabine Loewer, Yuin-Han Loh, In Hyun Park, Tamer Onder, Philip D Manos, Sumon Datta, Thorsten M Schlaeger & George Q Daley

  5. The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Moran N Cabili, Mitchell Guttman, Kelly Thomas, Manuel Garber, Eric S Lander & John L Rinn

  6. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA

    Moran N Cabili & Eric S Lander

  7. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Mitchell Guttman & Eric S Lander

  8. Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Kelly Thomas & George Q Daley

  9. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA

    George Q Daley

  10. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA

    John L Rinn

  11. Department of Pathology, Beth Israel and Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    John L Rinn

Authors
  1. Sabine Loewer

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Contributions

Co-direction of the project: G.Q.D. and J.L.R. Study concept and design: G.Q.D., J.L.R. and S.L. LincRNA array design: M. Guttman and J.L.R. iPSC generation and characterization: I.H.P., S.L., T.O., S.A. and P.D.M. LincRNA array hybridization, lincRNA and protein-coding gene expression analysis: M.N.C., K.T., M. Guttman, S.L. and M. Garber. Computational studies: M.N.C., M. Guttman and M. Garber. LincRNA transcriptional regulation: S.L. ChIP assays: Y.-H.L. LincRNA loss-of-function and gain-of-function studies: S.L., M.C. and S.D. T.M.S. and E.S.L. provided essential ideas and suggestions on the manuscript. Manuscript preparation: G.Q.D., J.L.R. and S.L.

Corresponding authors

Correspondence toGeorge Q Daley orJohn L Rinn.

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The authors declare no competing financial interests.

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Supplementary Figures 1–14 and Supplementary Tables 1–4 (PDF 7895 kb)

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Loewer, S., Cabili, M., Guttman, M.et al. Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells.Nat Genet42, 1113–1117 (2010). https://doi.org/10.1038/ng.710

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