lincRNAs: de "lixo genômico" a "controladores do tráfego aéreo genômico"

Not 'Genomic Junk' After All: LincRNAs Have Global Role In Genome Regulation

ScienceDaily (July 20, 2009) — Earlier this year, a scientific team from Beth Israel Deaconess Medical Center (BIDMC) and the Broad Institute identified a class of RNA genes known as large intervening non-coding RNAs or "lincRNAs," a discovery that has pushed the field forward in understanding the roles of these molecules in many biological processes, including stem cell pluripotency, cell cycle regulation, and the innate immune response.

But even as one question was being answered, another was close on its heels: What, exactly, were these mysterious molecules doing?

They now appear to have found an important clue. Described in the July 14 issue of the Proceedings of the National Academy of Sciences (PNAS) the scientific team from BIDMC and the Broad Institute shows that lincRNAs – once dismissed as "genomic junk" – have a global role in genome regulation, ferrying proteins to assist their regulation at specific regions of the genome.

"I like to think of them as genetic air traffic controllers," explains co-senior author John Rinn, PhD, a Harvard Medical School Assistant Professor of Pathology at BIDMC and Associate Member of the Broad Institute. "It has long been a mystery as to how widely expressed proteins shape the fate of cells. How does the same protein know to regulate one genomic location in a brain cell and regulate a different genomic region in a liver cell? Our study suggests that in the same way that air traffic controllers organize planes in the air, lincRNAs may be organizing key chromatin complexes in the cell."

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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

+Author Affiliations

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

Contributed by Eric S. Lander, May 3, 2009

↵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.

histone modifications epigenetic regulation polycomb
Footnotes

2To whom correspondence may be addressed. E-mail: lander@broad.mit.edu or jrinn@broad.mit.edu

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.

The authors declare no conflict of interest.

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.

Freely available online through the PNAS open access option.

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