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lincRNAs act in the circuitry controlling pluripotency and differentiation

Guttman, Mitchell and Donaghey, Julie and Carey, Bryce W. and Garber, Manuel and Grenier, Jennifer K. and Munson, Glen and Young, Geneva and Bergstrom Lucas, Anne and Ach, Robert and Bruhn, Laurakay and Yang, Xiaoping and Amit, Ido and Meissner, Alexander and Regev, Aviv and Rinn, John L. and Root, David E. and Lander, Eric S. (2011) lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature, 477 (7364). pp. 295-300. ISSN 0028-0836. PMCID PMC3175327.

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Although thousands of large intergenic non-coding RNAs (lincRNAs) have been identified in mammals, few have been functionally characterized, leading to debate about their biological role. To address this, we performed loss-of-function studies on most lincRNAs expressed in mouse embryonic stem (ES) cells and characterized the effects on gene expression. Here we show that knockdown of lincRNAs has major consequences on gene expression patterns, comparable to knockdown of well-known ES cell regulators. Notably, lincRNAs primarily affect gene expression in trans. Knockdown of dozens of lincRNAs causes either exit from the pluripotent state or upregulation of lineage commitment programs. We integrate lincRNAs into the molecular circuitry of ES cells and show that lincRNA genes are regulated by key transcription factors and that lincRNA transcripts bind to multiple chromatin regulatory proteins to affect shared gene expression programs. Together, the results demonstrate that lincRNAs have key roles in the circuitry controlling ES cell state.

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URLURL TypeDescription CentralArticle ReadCube access
Guttman, Mitchell0000-0003-4748-9352
Regev, Aviv0000-0003-3293-3158
Lander, Eric S.0000-0003-2662-4631
Additional Information:© 2011 Macmillan Publishers Limited. Received 28 March 2011; Accepted 26 July 2011; Published online 28 August 2011. We thank D. Rivera, T. Green, T. Bhimdi, G. Verstappen, C. Surka, S. Silver, A. Brown, D. Lam and O. Ram for technical help; C. Gifford, S. Markoulaki and R. Jaenisch for providing cell lines used in this study; P. Tsang, B. Curry, A. Tsalenko and Agilent Technologies for microarray and technical help; B. Challis and Active Motif for antibodies; G. Geiss, R. Boykin and Nanostring technologies for technical help; E. Wang and C. Burge for help with RNA immunoprecipitation experiments and helpful discussions; P. Gupta, A. Gnirke, J. Cassady, E. Lieberman-Aiden, M. Cabili and M. Thompson for discussions and ideas; and L. Gaffney for assistance with figures. M. Guttman is a Vertex scholar. This work was funded by NHGRI, a Center for Excellence for Genomic Science, the Merkin Foundation for Stem Cell Research, and funds from the Broad Institute of MIT and Harvard.
Funding AgencyGrant Number
National Human Genome Research InstituteUNSPECIFIED
Richard Merkin Foundation for Stem Cell ResearchUNSPECIFIED
Broad Institute of MIT and HarvardUNSPECIFIED
Issue or Number:7364
PubMed Central ID:PMC3175327
Record Number:CaltechAUTHORS:20161121-153838401
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Official Citation:lincRNAs act in the circuitry controlling pluripotency and differentiation Mitchell Guttman, Julie Donaghey, Bryce W. Carey, Manuel Garber, Jennifer K. Grenier, Glen Munson, Geneva Young, Anne Bergstrom Lucas, Robert Ach, Laurakay Bruhn, Xiaoping Yang, Ido Amit, Alexander Meissner, Aviv Regev, John L. Rinn, David E. Root & Eric S. Lander Nature 477, 295–300 (15 September 2011) doi:10.1038/nature10398
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:72216
Deposited By: Tony Diaz
Deposited On:21 Nov 2016 23:49
Last Modified:09 Mar 2020 13:19

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