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Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription


With the recent recognition of non-coding RNAs (ncRNAs) flanking many genes1,2,3,4,5, a central issue is to obtain a full understanding of their potential roles in regulated gene transcription programmes, possibly through different mechanisms6,7,8,9,10,11,12. Here we show that an RNA-binding protein, TLS (for translocated in liposarcoma), serves as a key transcriptional regulatory sensor of DNA damage signals that, on the basis of its allosteric modulation by RNA, specifically binds to and inhibits CREB-binding protein (CBP) and p300 histone acetyltransferase activities on a repressed gene target, cyclin D1 (CCND1) in human cell lines. Recruitment of TLS to the CCND1 promoter to cause gene-specific repression is directed by single-stranded, low-copy-number ncRNA transcripts tethered to the 5′ regulatory regions of CCND1 that are induced in response to DNA damage signals. Our data suggest that signal-induced ncRNAs localized to regulatory regions of transcription units can act cooperatively as selective ligands, recruiting and modulating the activities of distinct classes of RNA-binding co-regulators in response to specific signals, providing an unexpected ncRNA/RNA-binding protein-based strategy to integrate transcriptional programmes.

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Figure 1: TLS is a specific inhibitor of CBP and p300 HAT activity.
Figure 2: Consensus GGUG-containing RNA oligonucleotide promotes the inhibitory effect of TLS on CBP and p300 HAT activities.
Figure 3: TLS negatively regulates the CBP and p300 HAT-regulated CCND1 gene.
Figure 4: ncRNA CCND1 s are predominantly single-stranded, DNA-bound species that bind to TLS.
Figure 5: ncRNA CCND1 negatively regulates CCND1 transcription by recruiting TLS to the CCND1 promoter.

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  1. Kapranov, P., Willingham, A. T. & Gingeras, T. R. Genome-wide transcription and the implications for genomic organization. Nature Rev. Genet. 8, 413–423 (2007)

    Article  CAS  Google Scholar 

  2. Bernstein, E. & Allis, C. D. RNA meets chromatin. Genes Dev. 19, 1635–1655 (2005)

    Article  CAS  Google Scholar 

  3. Carninci, P. et al. The transcriptional landscape of the mammalian genome. Science 309, 1559–1563 (2005)

    Article  CAS  ADS  Google Scholar 

  4. Bertone, P. et al. Global identification of human transcribed sequences with genome tiling arrays. Science 306, 2242–2246 (2004)

    Article  CAS  ADS  Google Scholar 

  5. Mattick, J. S. & Makunin, I. V. Non-coding RNA. Hum. Mol. Genet. 15 (Spec. Iss. 1) R17–R29 (2006)

    Article  CAS  Google Scholar 

  6. Martianov, I., Ramadass, A., Serra Barros, A., Chow, N. & Akoulitchev, A. Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature 445, 666–670 (2007)

    Article  CAS  Google Scholar 

  7. Rinn, J. L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007)

    Article  CAS  Google Scholar 

  8. Feng, J. et al. The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes Dev. 20, 1470–1484 (2006)

    Article  CAS  Google Scholar 

  9. Petruk, S. et al. Transcription of bxd noncoding RNAs promoted by Trithorax represses Ubx in cis by transcriptional interference. Cell 127, 1209–1221 (2006)

    Article  CAS  Google Scholar 

  10. Sanchez-Elsner, T., Gou, D., Kremmer, E. & Sauer, F. Noncoding RNAs of trithorax response elements recruit Drosophila Ash1 to Ultrabithorax. Science 311, 1118–1123 (2006)

    Article  CAS  ADS  Google Scholar 

  11. Lanz, R. B. et al. A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell 97, 17–27 (1999)

    Article  CAS  Google Scholar 

  12. O’Neill, M. J. The influence of non-coding RNAs on allele-specific gene expression in mammals. Hum. Mol. Genet. 14 (Spec. Iss. 1) R113–R120 (2005)

    Article  Google Scholar 

  13. Rosenfeld, M. G., Lunyak, V. V. & Glass, C. K. Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev. 20, 1405–1428 (2006)

    Article  CAS  Google Scholar 

  14. McKenna, N. J. & O’Malley, B. W. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108, 465–474 (2002)

    Article  CAS  Google Scholar 

  15. Seo, S. B. et al. Regulation of histone acetylation and transcription by INHAT, a human cellular complex containing the set oncoprotein. Cell 104, 119–130 (2001)

    Article  CAS  Google Scholar 

  16. Sebastiaan Winkler, G. et al. Isolation and mass spectrometry of transcription factor complexes. Methods 26, 260–269 (2002)

    Article  CAS  Google Scholar 

  17. Uranishi, H. et al. Involvement of the pro-oncoprotein TLS (translocated in liposarcoma) in nuclear factor-κB p65-mediated transcription as a coactivator. J. Biol. Chem. 276, 13395–13401 (2001)

    Article  CAS  Google Scholar 

  18. Yang, L., Embree, L. J., Tsai, S. & Hickstein, D. D. Oncoprotein TLS interacts with serine-arginine proteins involved in RNA splicing. J. Biol. Chem. 273, 27761–27764 (1998)

    Article  CAS  Google Scholar 

  19. Hicks, G. G. et al. Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nature Genet. 24, 175–179 (2000)

    Article  CAS  Google Scholar 

  20. Kuroda, M. et al. Male sterility and enhanced radiation sensitivity in TLS-/- mice. EMBO J. 19, 453–462 (2000)

    Article  CAS  Google Scholar 

  21. Baechtold, H. et al. Human 75-kDa DNA-pairing protein is identical to the pro-oncoprotein TLS/FUS and is able to promote D-loop formation. J. Biol. Chem. 274, 34337–34342 (1999)

    Article  CAS  Google Scholar 

  22. Bertrand, P., Akhmedov, A. T., Delacote, F., Durrbach, A. & Lopez, B. S. Human POMp75 is identified as the pro-oncoprotein TLS/FUS: both POMp75 and POMp100 DNA homologous pairing activities are associated to cell proliferation. Oncogene 18, 4515–4521 (1999)

    Article  CAS  Google Scholar 

  23. Ron, D. TLS-CHOP and the role of RNA-binding proteins in oncogenic transformation. Curr. Top. Microbiol. Immunol. 220, 131–142 (1997)

    MathSciNet  CAS  PubMed  Google Scholar 

  24. Kurokawa, R. et al. Differential use of CREB binding protein-coactivator complexes. Science 279, 700–703 (1998)

    Article  CAS  ADS  Google Scholar 

  25. Lerga, A. et al. Identification of an RNA binding specificity for the potential splicing factor TLS. J. Biol. Chem. 276, 6807–6816 (2001)

    Article  CAS  Google Scholar 

  26. Miyakawa, Y. & Matsushime, H. Rapid downregulation of cyclin D1 mRNA and protein levels by ultraviolet irradiation in murine macrophage cells. Biochem. Biophys. Res. Commun. 284, 71–76 (2001)

    Article  CAS  Google Scholar 

  27. Impey, S. et al. Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119, 1041–1054 (2004)

    CAS  PubMed  Google Scholar 

  28. Murata, T. et al. Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in Rubinstein–Taybi syndrome. Hum. Mol. Genet. 10, 1071–1076 (2001)

    Article  CAS  Google Scholar 

  29. Agami, R. & Bernards, R. Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Cell 102, 55–66 (2000)

    Article  CAS  Google Scholar 

  30. Korzus, E. et al. Transcription factor-specific requirements for coactivators and their acetyltransferase functions. Science 279, 703–707 (1998)

    Article  CAS  ADS  Google Scholar 

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We thank A. Gettings for help with mass spectrometric analysis; M. Hiramatsu, W. Sato and C. Nelson for technical assistance; A. Matsushita, M. Matsubara and T. Oyoshi for discussion; and J. Hightower and M. Fisher for figure and manuscript preparation. This work was supported by the Fujisawa Foundation, the Takeda Science Foundation, the Naito Foundation, Sankyo Foundation Life Science, and grants-in-aid (nos 17054036 and 18055029) from the Ministry of Education, Culture, Sports, Science, and Technology in Japan to R.K., by National Institutes of Health grants CA52599 and HL59694 to C.K.G., by National Cancer Institute Cancer Center Support grant P30 CA08748 to P.T., by NS34934, DK39949 and CA097134 to M.G.R., and by DK074868 to C.K.G. and M.G.R. M.G.R. is a Howard Hughes Medical Institute investigator.

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Correspondence to Michael G. Rosenfeld, Christopher K. Glass or Riki Kurokawa.

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Wang, X., Arai, S., Song, X. et al. Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454, 126–130 (2008).

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