Abstract
The majority of the human genome is found to be transcribed and generates mostly noncoding (nc) RNAs that do not possess protein information. MicroRNAs are one of the well-identified small ncRNAs, but occupy merely a fraction of ncRNAs. Long (large) ncRNAs are emerging as a novel class of ncRNAs, but knowledge of these ncRNAs is far less accumulated. Long ncRNAs are tentatively classified as an ncRNA species containing more than 200 nucleotides. Recently, a long promoter-associated ncRNA (pncRNA) has been identified to be transcribed from the cyclin D1 promoter upon induction by genotoxic factors like ionizing-irradiation. The cyclin D1 pncRNA is specifically bound with an RNA-binding protein TLS (Translocated in liposarcoma) and exerts transcriptional repression through histone acetyltransferase (HAT) inhibitory activity. Analysis of TLS and the pncRNAs could provide a model for elucidating their roles inregulation of mammalian transcriptional programs. The pncRNA binding to TLS turns out to be an essential event for the HAT inhibitory activity. A key consensus sequence of the pncRNA is composed of GGUG, while not every RNA sequence bearing GGUG is targeted by TLS, suggesting that a secondary structure of the GGUG-bearing RNAs is also involved in recognition by TLS. Taken together, TLS is a unique mediator between signals of the long ncRNAs and transcription, suggesting that RNA networking functions in living cells.1–3
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References
Pawlicki JM, Steitz JA. Nuclear networking fashions premessenger RNA and primary microRNA transcripts for function. Trends Cell Biol 2009; 20:52–61.
Collins LJ, Penny D. The RNA infrastructure: dark matter of the eukaryotic cell? Trends Genet 2009; 25:120–128.
Siomi H, Siomi MC. On the road to reading the RNA-interference code. Nature 2009; 457:396–404.
ENCODE-consortium. The ENCODE (ENCyclopedia OfDNA Elements) Project. Science 2004; 306:636–640.
Carninci P, Kasukawa T, Katayama S et al. The transcriptional landscape of the mammalian genome. Science 2005; 309:1559–1563.
Bertone P, Stolc V, Royce TE et al. Global identification of human transcribed sequences with genome tiling arrays. Science 2004; 306:2242–2246.
Willingham AT, Orth AP, Batalov S et al. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 2005; 309:1570–1573.
Fire A, Xu S, Montgomery MK et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998; 391:806–811.
Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of posttranscriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 2008; 9:102–114.
Lanz RB, McKenna NJ, Onate SA et al. A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell 1999; 97:17–27.
Feng J, Bi C, Clark BS et al. The Evf-2 noncoding RNA is transcribed from the Dix-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes Dev 2006; 20:1470–1484.
Rinn JL, Kertesz M, Wang JK et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 2007; 129:1311–1323.
Yu W, Gius D, Onyango P et al. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 2008; 451:202–206.
Wang X, Arai S, Song X et al. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 2008; 454:126–130.
Crozat A, Aman P, Mandahl N et al. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 1993; 363:640–644.
Kuroda M, Sok J, Webb L et al. Male sterility and enhanced radiation sensitivity in TLS(-/-) mice. EMBO J2000; 19:453–462.
Hicks GG, Singh N, Nashabi A et al. Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nat Genet 2000; 24:175–179.
Delattre O, Zucman J, Plougastel B et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 1992; 359:162–165.
Bertolotti A, Lutz Y, Heard DJ et al. hTAF(II)68, a novel RNA/ssDNA-binding protein with homology to the pro-oncoproteins TLS/FUS and EWS is associated with both TFIID and RNA polymerase II. EMBO J 1996; 15:5022–5031.
Bertolotti A, Bell B, Tora L. The N-terminal domain of human TAFII68 displays transactivation and oncogenic properties. Oncogene 1999; 18:8000–8010.
Attwooll C, Tariq M, Harris M et al. Identification of a novel fusion gene involving hTAFII68 and CHN from a t(9;17)(q22;q11.2) translocation in an extraskeletal myxoid chondrosarcoma. Oncogene 1999; 18:7599–7601.
Ladanyi M. The emerging molecular genetics of sarcoma translocations. Diagn Mol Pathol 1995; 4:162–173.
Riggi N, Cironi L, Provero P et al. Expression of the FUS-CHOP fusion protein in primary mesenchymal progenitor cells gives rise to a model of myxoid liposarcoma. Cancer Res 2006; 66:7016–7023.
Lerga A, Hallier M, Delva L et al. Identification of an RNA binding specificity for the potential splicing factor TLS. J Biol Chem 2001; 276:6807–6816.
Miyakawa Y, Matsushime H. Rapid downregulation of cyclin D1 mRNA and protein levels by ultraviolet irradiation in murine macrophage cells. Biochem Biophys Res Commun 2001; 284:71–76.
Guttman M, Amit I, Garber M et al. Chromatin signature reveals over a thousand highly conserved large noncoding RNAs in mammals. Nature 2009; 458:223–227.
Khalil AM, Guttman M, Huarte M et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci USA 2009; 106:11667–11672.
Huarte M, Guttman M, Feldser D et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 2010; 142:409–419.
Iko Y, Kodama TS, Kasai N et al. Domain architectures and characterization of an RNA-binding protein, TLS. J Biol Chem 2004; 279:44834–44840.
Kapranov P, Cheng J, Dike S et al. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 2007; 316:1484–1488.
Wang P, Yin S, Zhang Z et al. Evidence for common short natural trans sense-antisense pairing between transcripts from protein coding genes. Genome Biol 2008; 9:R169.
Zinszner H, Albalat R, Ron D. A novel effector domain from the RNA-binding protein TLS or EWS is required for oncogenic transformation by CHOP. Genes Dev 1994; 8:2513–2526.
Prasad DD, Ouchida M, Lee L et al. TLS/FUS fusion domain of TLS/FUS-erg chimeric protein resulting from the t(16;21) chromosomal translocation in human myeloid leukemia functions as a transcriptional activation domain. Oncogene 1994; 9:3717–3729.
Loughlin FE, Mansfield RE, Vaz PM et al. The zinc fingers of the SR-like protein ZRANB2 are single-stranded RNA-binding domains that recognize 5′ splice site-like sequences. Proc Natl Acad Sci USA 2009; 106:5581–5586.
Martianov I, Ramadass A, Serra Barros A et al. Repression of the human dihydrofolate reductase gene by a noncoding interfering transcript. Nature 2007; 445:666–670.
Kim TK, Hemberg M, Gray JM et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 2010; 465:182–187.
Ayoubi TA, Van De Ven WJ. Regulation of gene expression by alternative promoters. FASEB J 1996; 10:453–460.
Martens JA, Laprade L, Winston F. Intergenic transcription is required to repress the Saccharomyces cerevisiae SER3 gene. Nature 2004; 429:571–574.
Impey S, McCorkle SR, Cha-Molstad H et al. Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 2004; 119:1041–1054.
An W, Kim J, Roeder RG. Ordered cooperative functions of PRMT1, p300 and CARM1 in transcriptional activation by p53. Cell 2004; 117:735–748.
Kurokawa R, Rosenfeld MG, Glass CK. Transcriptional regulation through noncoding RNAs and epigenetic modifications. RNA Biol 2009; 6:233–236.
Kwiatkowski TJ Jr, Bosco DA, Leclerc AL et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 2009; 323:1205–1208.
Vance C, Rogelj B, Hortobágyi T et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 2009; 323:1208–1211.
Van Langenhove T, van der Zee J, Sleegers K et al. Genetic contribution of FUS to frontotemporal lobar degeneration. Neurology 2010; 74:366–371.
Lagier-Tourenne C, Cleveland DW. Rethinking ALS: the FUS about TDP-43. Cell 2009; 136:1001–1004.
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Kurokawa, R. (2011). Promoter-Associated Long Noncoding RNAs Repress Transcription Through a RNA Binding Protein TLS. In: Collins, L.J. (eds) RNA Infrastructure and Networks. Advances in Experimental Medicine and Biology, vol 722. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0332-6_12
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DOI: https://doi.org/10.1007/978-1-4614-0332-6_12
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