Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression
- Ahmad M. Khalila,b,1,
- Mitchell Guttmana,c,1,
- Maite Huartea,b,
- Manuel Garbera,
- Arjun Rajd,
- Dianali Rivea Moralesa,b,
- Kelly Thomasa,b,
- Aviva Pressera,
- Bradley E. Bernsteina,e,
- Alexander van Oudenaardend,
- Aviv Regeva,c,
- Eric S. Landera,c,f,1,2 and
- John L. Rinna,b,1,2
- aThe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142;
- bDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
- Departments of cBiology and
- dPhysics, Massachusetts Institute of Technology, Cambridge, MA 02139;
- eMolecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129; and
- fDepartment of Systems Biology, Harvard Medical School, Boston, MA 02114
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Contributed by Eric S. Lander, May 3, 2009
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↵1A.M.K., M. Guttman, E.S.L., and J.L.R. contributed equally to this work. (received for review March 15, 2009)
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.
Footnotes
- 2To whom correspondence may be addressed. E-mail: lander{at}broad.mit.edu or jrinn{at}broad.mit.edu
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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.
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The authors declare no conflict of interest.
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Data deposition: The sequence reported in this paper has been deposited in the GEO database (accession no. GSE16226).
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This article contains supporting information online at www.pnas.org/cgi/content/full/0904715106/DCSupplemental.
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Freely available online through the PNAS open access option.
