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      Long Noncoding RNA as Modular Scaffold of Histone Modification Complexes

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          A Lot of HOTAIR

          The roles of several classes of small (<50 nucleotides) noncoding RNAs are beginning to be defined in molecular detail, whereas the function of most of the long (∼200+ nucleotides), intergenic noncoding (linc)RNAs found in most eukaryotic genomes remains something of a mystery. The HOTAIR lincRNA, which is transcribed from the mouse HOXC locus, binds to the Polycomb Repressive Complex 2 (PRC2) and recruits it to HOXD and other genes, where its histone methylase activity acts to repress gene transcription. Tsai et al. (p. [Related article:]689 , published online 8 July) now show that HOTAIR also binds to a histone demethylase enzyme, LSD1, part of the CoREST/REST repressor complex. LSD1 acts to remove transcription-activating histone marks, reinforcing the repressive activity of the PRC2 complex. HOTAIR thus functions as a platform for the coordinated binding of PRC2 and LSD1-containing complexes to genes, as revealed in a genome-wide analysis of PRC1/CoREST/REST co-regulated genes.

          Abstract

          The long noncoding RNA HOTAIR binds two distinct protein complexes that modify chromatin and repress transcription.

          Abstract

          Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5′ domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3′ domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.

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          Most cited references27

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          Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

          Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.
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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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              Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis

              Large intervening noncoding RNAs (lincRNAs) are pervasively transcribed in the genome1, 2, 3 yet their potential involvement in human disease is not well understood4,5. 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 activities6,7,8. 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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                Author and article information

                Journal
                Science
                Science
                American Association for the Advancement of Science (AAAS)
                0036-8075
                1095-9203
                August 06 2010
                August 06 2010
                : 329
                : 5992
                : 689-693
                Affiliations
                [1 ]Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
                [2 ]Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel.
                [3 ]Department of Pathology, Harvard Medical School, and Division of New Born Medicine, Department of Medicine, Children’s Hospital Boston, Boston, MA 02138, USA.
                [4 ]Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, MA 02142, USA.
                Article
                10.1126/science.1192002
                2967777
                20616235
                9678118b-f6d4-4636-89f6-4af546d22df9
                © 2010
                History

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