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      Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis

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          Abstract

          Large intervening noncoding RNAs (lincRNAs) are pervasively transcribed in the genome 1, 2, 3 yet their potential involvement in human disease is not well understood 4, 5. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodeling activities 6, 7, 8. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumors and metastases, and HOTAIR expression level in primary tumors is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb Repressive Complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings suggest that lincRNAs play active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.

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          Most cited references 30

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          Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.

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            Cluster analysis and display of genome-wide expression patterns.

            A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression. The output is displayed graphically, conveying the clustering and the underlying expression data simultaneously in a form intuitive for biologists. We have found in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function, and we find a similar tendency in human data. Thus patterns seen in genome-wide expression experiments can be interpreted as indications of the status of cellular processes. Also, coexpression of genes of known function with poorly characterized or novel genes may provide a simple means of gaining leads to the functions of many genes for which information is not available currently.
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              Evolution and functions of long noncoding RNAs.

              RNA is not only a messenger operating between DNA and protein. Transcription of essentially the entire eukaryotic genome generates a myriad of non-protein-coding RNA species that show complex overlapping patterns of expression and regulation. Although long noncoding RNAs (lncRNAs) are among the least well-understood of these transcript species, they cannot all be dismissed as merely transcriptional "noise." Here, we review the evolution of lncRNAs and their roles in transcriptional regulation, epigenetic gene regulation, and disease.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                9 March 2010
                15 April 2010
                8 March 2011
                : 464
                : 7291
                : 1071-1076
                Affiliations
                [1 ] Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
                [2 ] Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
                [3 ] Stanford Comprehensive Cancer Center and Transgenic Mouse Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA
                [4 ] Dept. of Pathology, Academic Medical Center, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands
                [5 ] Dept. of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
                [6 ] The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA
                [7 ] Applied Biosystems, Foster City, CA 94404, USA
                [8 ] Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
                Author notes
                Correspondence and request for materials should beaddressed to H.Y.C. ( howchang@ 123456stanford.edu )
                Article
                nihpa183311
                10.1038/nature08975
                3049919
                20393566

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funding
                Funded by: National Human Genome Research Institute : NHGRI
                Funded by: National Cancer Institute : NCI
                Award ID: R01 HG004361-03 ||HG
                Funded by: National Human Genome Research Institute : NHGRI
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA118750-03 ||CA
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