Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression
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.
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.Attached Files
Published - PNAS-2009-Khalil-11667-72.pdf
Supplemental Material - 0904715106SI.pdf
Supplemental Material - SD1.xls
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Additional details
- PMCID
- PMC2704857
- Eprint ID
- 72208
- Resolver ID
- CaltechAUTHORS:20161121-140449068
- HL007893
- NIH
- Vertex Scholarship
- Damon Runyon-Rachleff Innovation and Smith Family Foundation Scholarship
- Richard Merkin Foundation for Stem Cell Research
- Burroughs Wellcome Fund
- National Human Genome Research Institute
- Broad Institute of MIT and Harvard
- Created
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2016-11-21Created from EPrint's datestamp field
- Updated
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2021-11-11Created from EPrint's last_modified field