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Extensive and coordinated transcription of noncoding RNAs within cell cycle promoters

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      Abstract

      Transcription of long noncoding RNAs (lncRNAs) within gene regulatory elements can modulate gene activity in response to external stimuli, but the scope and functions of such activity are not known. Here we use an ultra-high density array that tiles the promoters of 56 cell cycle genes to interrogate 108 samples representing diverse perturbations. We identify 216 transcribed regions that encode putative lncRNAs--many with RT-PCR-validated periodic expression during the cell cycle, show altered expression in human cancers, and are regulated in expression by specific oncogenic stimuli, stem cell differentiation, or DNA damage. DNA damage induces five lncRNAs from the CDKN1A promoter, and one such lncRNA, named PANDA, is induced in a p53- dependent manner. PANDA interacts with the transcription factor NF-YA to limit expression of pro-apoptotic genes; PANDA depletion markedly sensitized human fibroblasts to apoptosis by doxorubicin. These findings suggest potentially widespread roles for promoter lncRNAs in cell growth control.

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      Most cited references 54

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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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        MicroRNAs: small RNAs with a big role in gene regulation.

         Sai-Lin He,  G Hannon (2004)
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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

            Affiliations
            [1 ]Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA
            [2 ]Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305.
            [3 ]Life Technologies, Foster City, California 94404, USA
            [4 ]The Broad Institute, Cambridge, Massachusetts 02142, USA
            [5 ]Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
            [6 ]Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC27599, USA
            [7 ]Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
            [8 ]Department of Biochemistry 1, Hamamatsu University School of Medicine, Higashi-ku, Hamamatsu 431-3192, Japan.
            [9 ]Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
            [10 ]Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands
            [11 ]Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
            [12 ]Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
            [13 ]Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
            [14 ]Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, 0310 Oslo, Norway
            [15 ]Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
            Author notes
            Corresponding authors: D.J.W. ( davewong@ 123456stanford.edu ) and H.Y.C. ( howchang@ 123456stanford.edu )
            [*]

            These authors equally contributed to this work.

            Journal
            9216904
            2419
            Nat Genet
            Nat. Genet.
            Nature genetics
            1061-4036
            1546-1718
            22 March 2013
            05 June 2011
            13 May 2013
            : 43
            : 7
            : 621-629
            21642992
            3652667
            10.1038/ng.848
            NIHMS294610

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            Funding
            Funded by: National Cancer Institute : NCI
            Award ID: R01 CA130795-05 || CA
            Funded by: National Cancer Institute : NCI
            Award ID: R01 CA130795 || CA
            Funded by: National Cancer Institute : NCI
            Award ID: R01 CA118750 || CA
            Categories
            Article

            Genetics

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