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Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression

Khalil, Ahmad M. and Guttman, Mitchell and Huarte, Maite and Garber, Manuel and Raj, Arjun and Morales, Dianali Rivea and Thomas, Kelly and Presser, Aviva and Bernstein, Bradley E. and van Oudenaarden, Alexander and Regev, Aviv and Lander, Eric S. and Rinn, John L. (2009) Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proceedings of the National Academy of Sciences of the United States of America, 106 (28). pp. 11667-11672. ISSN 0027-8424. PMCID PMC2704857. https://resolver.caltech.edu/CaltechAUTHORS:20161121-140449068

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Abstract

We recently showed that the mammalian genome encodes >1,000 large intergenic noncoding (linc)RNAs that are clearly conserved across mammals and, thus, functional. Gene expression patterns have implicated these lincRNAs in diverse biological processes, including cell-cycle regulation, immune surveillance, and embryonic stem cell pluripotency. However, the mechanism by which these lincRNAs function is unknown. Here, we expand the catalog of human lincRNAs to ≈3,300 by analyzing chromatin-state maps of various human cell types. Inspired by the observation that the well-characterized lincRNA HOTAIR binds the polycomb repressive complex (PRC)2, we tested whether many lincRNAs are physically associated with PRC2. Remarkably, we observe that ≈20% of lincRNAs expressed in various cell types are bound by PRC2, and that additional lincRNAs are bound by other chromatin-modifying complexes. Also, we show that siRNA-mediated depletion of certain lincRNAs associated with PRC2 leads to changes in gene expression, and that the up-regulated genes are enriched for those normally silenced by PRC2. We propose a model in which some lincRNAs guide chromatin-modifying complexes to specific genomic loci to regulate gene expression.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.0904715106DOIArticle
http://www.pnas.org/content/106/28/11667PublisherArticle
http://www.pnas.org/content/106/28/11667?tab=dsPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704857/PubMed CentralArticle
ORCID:
AuthorORCID
Guttman, Mitchell0000-0003-4748-9352
Regev, Aviv0000-0003-3293-3158
Lander, Eric S.0000-0003-2662-4631
Additional Information:© 2009 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Eric S. Lander, May 3, 2009 (sent for review March 15, 2009). Published ahead of print July 1, 2009. We thank Yang Shi and Shigeki Iwase (Harvard Medical School) for antibodies to SMCX and their input on the manuscript; J. P. Mesirov and Pablo Tamayo [The Broad Institute of Harvard and Massachusetts Institute of Technology (MIT)] for discussions and statistical insights; and Miguel Rivera for access to hEK ChIP-Seq data. A.M.K. is supported by National Institutes of Health Training Grant HL007893. M. Guttman is a Vertex scholar. J.L.R is a Damon Runyon-Rachleff Innovation and Smith Family Foundation Scholar. J.L.R. and A. Regev are Investigators of the Richard Merkin Foundation for Stem Cell Research at the Broad Institute. A.R. is supported by the Pioneer award and by the Burroughs Wellcome Fund. This work was supported by the National Human Genome Research Institute, and the Broad Institute of MIT and Harvard. Author contributions: A.M.K., M. Guttman, E.S.L., and J.L.R. designed research; A.M.K., M. Guttman, M.H., A. Raj, D.R.M., and K.T. performed research; A.M.K., M. Guttman, A.P., B.E.B., A.v.O., A. Regev, E.S.L., and J.L.R. contributed new reagents/analytic tools; A.M.K., M. Guttman, M. Garber, E.S.L., and J.L.R. analyzed data; and A.M.K., M. Guttman, A. Regev, E.S.L., and J.L.R. wrote the paper. Data deposition: The sequence reported in this paper has been deposited in the GEO database (accession no. GSE16226). This article contains supporting information online at www.pnas.org/cgi/content/full/0904715106/DCSupplemental. The authors declare no conflict of interest.
Funders:
Funding AgencyGrant Number
NIHHL007893
Vertex ScholarshipUNSPECIFIED
Damon Runyon-Rachleff Innovation and Smith Family Foundation ScholarshipUNSPECIFIED
Richard Merkin Foundation for Stem Cell ResearchUNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
National Human Genome Research InstituteUNSPECIFIED
Broad Institute of MIT and HarvardUNSPECIFIED
Subject Keywords:histone modifications; epigenetic regulation; polycomb
Issue or Number:28
PubMed Central ID:PMC2704857
Record Number:CaltechAUTHORS:20161121-140449068
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20161121-140449068
Official Citation:Ahmad M. Khalil, Mitchell Guttman, Maite Huarte, Manuel Garber, Arjun Raj, Dianali Rivea Morales, Kelly Thomas, Aviva Presser, Bradley E. Bernstein, Alexander van Oudenaarden, Aviv Regev, Eric S. Lander, and John L. Rinn Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression PNAS 2009 106 (28) 11667-11672; published ahead of print July 1, 2009, doi:10.1073/pnas.0904715106
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:72208
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:21 Nov 2016 22:23
Last Modified:09 Mar 2020 13:19

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