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

Loewer, Sabine and Cabili, Moran N. and Guttman, Mitchell and Loh, Yuin-Han and Thomas, Kelly and Park, In Hyun and Garber, Manuel and Curran, Matthew and Onder, Tamer and Agarwal, Suneet and Manos, Philip D. and Datta, Sumon and Lander, Eric S. and Schlaeger, Thorsten M and Daley, George Q. and Rinn, John L. (2010) Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nature Genetics, 42 (12). pp. 1113-1117. ISSN 1061-4036. PMCID PMC3040650.

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The conversion of lineage-committed cells to induced pluripotent stem cells (iPSCs) by reprogramming is accompanied by a global remodeling of the epigenome, resulting in altered patterns of gene expression. Here we characterize the transcriptional reorganization of large intergenic non-coding RNAs (lincRNAs) 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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Guttman, Mitchell0000-0003-4748-9352
Lander, Eric S.0000-0003-2662-4631
Additional Information:© 2010 Macmillan Publishers Limited. Received 25 May; accepted 18 September; published online 7 November 2010; corrected after print 3 December 2010. 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 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. The authors declare no competing financial interests.
Funding AgencyGrant Number
Damon Runyon-Rachleff AwardUNSPECIFIED
Searle Scholars ProgramUNSPECIFIED
Smith Family FoundationUNSPECIFIED
Richard Merkin Foundation for Stem Cell ResearchUNSPECIFIED
Human Frontier Science ProgramUNSPECIFIED
Agency for Science, Technology and Research (A*STAR)UNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIH1 RC2-HL102815
Issue or Number:12
PubMed Central ID:PMC3040650
Record Number:CaltechAUTHORS:20161122-075138398
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Official Citation:Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells Sabine Loewer, Moran N Cabili, Mitchell Guttman, Yuin-Han Loh, Kelly Thomas, In Hyun Park, Manuel Garber, Matthew Curran, Tamer Onder, Suneet Agarwal, Philip D Manos, Sumon Datta, Eric S Lander, Thorsten M Schlaeger, George Q Daley & John L Rinn Nature Genetics 42, 1113–1117 (2010) doi:10.1038/ng.710
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:72233
Deposited By: Tony Diaz
Deposited On:22 Nov 2016 18:18
Last Modified:09 Mar 2020 13:18

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