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Control of somatic tissue differentiation by the long non-coding RNA TINCR

Abstract

Several of the thousands of human long non-coding RNAs (lncRNAs) have been functionally characterized1,2,3,4; however, potential roles for lncRNAs in somatic tissue differentiation remain poorly understood. Here we show that a 3.7-kilobase lncRNA, terminal differentiation-induced ncRNA (TINCR), controls human epidermal differentiation by a post-transcriptional mechanism. TINCR is required for high messenger RNA abundance of key differentiation genes, many of which are mutated in human skin diseases, including FLG, LOR, ALOXE3, ALOX12B, ABCA12, CASP14 and ELOVL3. TINCR-deficient epidermis lacked terminal differentiation ultrastructure, including keratohyalin granules and intact lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs. TINCR–mRNA interaction occurs through a 25-nucleotide ‘TINCR box’ motif that is strongly enriched in interacting mRNAs and required for TINCR binding. A high-throughput screen to analyse TINCR binding capacity to approximately 9,400 human recombinant proteins revealed direct binding of TINCR RNA to the staufen1 (STAU1) protein. STAU1-deficient tissue recapitulated the impaired differentiation seen with TINCR depletion. Loss of UPF1 and UPF2, both of which are required for STAU1-mediated RNA decay, however, did not have differentiation effects. Instead, the TINCR–STAU1 complex seems to mediate stabilization of differentiation mRNAs, such as KRT80. These data identify TINCR as a key lncRNA required for somatic tissue differentiation, which occurs through lncRNA binding to differentiation mRNAs to ensure their expression.

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Figure 1: TINCR is induced during epidermal differentiation.
Figure 2: TINCR regulates epidermal differentiation genes involved in barrier formation.
Figure 3: TINCR interacts with differentiation mRNAs and STAU1 protein.
Figure 4: Differentiation regulation by TINCR RNA and STAU1 protein.

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Primary accessions

Gene Expression Omnibus

Data deposits

Sequence and array data are deposited in the Gene Expression Omnibus database under the accession number GSE35468.

References

  1. Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223–227 (2009)

    Article  ADS  CAS  Google Scholar 

  2. Khalil, A. M. et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl Acad. Sci. USA 106, 11667–11672 (2009)

    Article  ADS  CAS  Google Scholar 

  3. 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 

  4. 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 

  5. Pauli, A., Rinn, J. L. & Schier, A. F. Non-coding RNAs as regulators of embryogenesis. Nature Rev. Genet. 12, 136–149 (2011)

    Article  CAS  Google Scholar 

  6. Wan, D. et al. Large-scale cDNA transfection screening for genes related to cancer development and progression. Proc. Natl Acad. Sci. USA 101, 15724–15729 (2004)

    Article  ADS  CAS  Google Scholar 

  7. Sen, G. L., Reuter, J. A., Webster, D. E., Zhu, L. & Khavari, P. A. DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature 463, 563–567 (2010)

    Article  ADS  CAS  Google Scholar 

  8. Truong, A. B., Kretz, M., Ridky, T. W., Kimmel, R. & Khavari, P. A. p63 regulates proliferation and differentiation of developmentally mature keratinocytes. Genes Dev. 20, 3185–3197 (2006)

    Article  CAS  Google Scholar 

  9. O’Driscoll, J. et al. A recurrent mutation in the loricrin gene underlies the ichthyotic variant of Vohwinkel syndrome. Clin. Exp. Dermatol. 27, 243–246 (2002)

    Article  Google Scholar 

  10. Smith, F. J. et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nature Genet. 38, 337–342 (2006)

  11. Virtanen, M., Smith, S. K., Gedde-Dahl, T., Jr, Vahlquist, A. & Bowden, P. E. Splice site and deletion mutations in keratin (KRT1 and KRT10) genes: unusual phenotypic alterations in Scandinavian patients with epidermolytic hyperkeratosis. J. Invest. Dermatol. 121, 1013–1020 (2003)

    Article  CAS  Google Scholar 

  12. Elias, P. M. Stratum corneum defensive functions: an integrated view. J. Invest. Dermatol. 125, 183–200 (2005)

    Article  CAS  Google Scholar 

  13. Eckl, K. M. et al. Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B. J. Invest. Dermatol. 129, 1421–1428 (2009)

    Article  CAS  Google Scholar 

  14. Sakai, K. et al. ABCA12 is a major causative gene for non-bullous congenital ichthyosiform erythroderma. J. Invest. Dermatol. 129, 2306–2309 (2009)

    Article  CAS  Google Scholar 

  15. Westerberg, R. et al. Role for ELOVL3 and fatty acid chain length in development of hair and skin function. J. Biol. Chem. 279, 5621–5629 (2004)

    Article  CAS  Google Scholar 

  16. Denecker, G. et al. Caspase-14 protects against epidermal UVB photodamage and water loss. Nature Cell Biol. 9, 666–674 (2007)

    Article  CAS  Google Scholar 

  17. Raj, A., van den Bogaard, P., Rifkin, S. A., van Oudenaarden, A. & Tyagi, S. Imaging individual mRNA molecules using multiple singly labeled probes. Nature Methods 5, 877–879 (2008)

    Article  CAS  Google Scholar 

  18. Chu, C., Qu, K., Zhong, F. L., Artandi, S. E. & Chang, H. Y. Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. Mol. Cell 44, 667–678 (2011)

    Article  CAS  Google Scholar 

  19. Huarte, M. et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142, 409–419 (2010)

    Article  CAS  Google Scholar 

  20. Nagano, T. et al. The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 322, 1717–1720 (2008)

    Article  ADS  CAS  Google Scholar 

  21. Tsai, M. C. et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 329, 689–693 (2010)

    Article  ADS  CAS  Google Scholar 

  22. Dugré-Brisson, S. et al. Interaction of Staufen1 with the 5′ end of mRNA facilitates translation of these RNAs. Nucleic Acids Res. 33, 4797–4812 (2005)

    Article  Google Scholar 

  23. Gong, C. & Maquat, L. E. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature 470, 284–288 (2011)

    Article  ADS  CAS  Google Scholar 

  24. Kiebler, M. A. et al. The mammalian staufen protein localizes to the somatodendritic domain of cultured hippocampal neurons: implications for its involvement in mRNA transport. J. Neurosci. 19, 288–297 (1999)

    Article  CAS  Google Scholar 

  25. St Johnston, D., Beuchle, D. & Nusslein-Volhard, C. Staufen, a gene required to localize maternal RNAs in the Drosophila egg. Cell 66, 51–63 (1991)

    Article  CAS  Google Scholar 

  26. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005)

    Article  ADS  CAS  Google Scholar 

  27. Furic, L., Maher-Laporte, M. & DesGroseillers, L. A genome-wide approach identifies distinct but overlapping subsets of cellular mRNAs associated with Staufen1- and Staufen2-containing ribonucleoprotein complexes. RNA 14, 324–335 (2008)

    Article  CAS  Google Scholar 

  28. Merino, E. J., Wilkinson, K. A., Coughlan, J. L. & Weeks, K. M. RNA structure analysis at single nucleotide resolution by selective 2'-hydroxyl acylation and primer extension (SHAPE). J. Am. Chem. Soc. 127, 4223–4231 (2005)

    Article  CAS  Google Scholar 

  29. Bond, A. M. et al. Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry. Nature Neurosci. 12, 1020–1027 (2009)

    Article  CAS  Google Scholar 

  30. Young, T. L., Matsuda, T. & Cepko, C. L. The noncoding RNA Taurine Upregulated Gene 1 is required for differentiation of the murine retina. Curr. Biol. 15, 501–512 (2005)

    Article  CAS  Google Scholar 

  31. Trapnell, C., Pachter, L. & Salzberg, S. L. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009)

    Article  CAS  Google Scholar 

  32. Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010)

    Article  CAS  Google Scholar 

  33. Bailey, T. L. et al. MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 37, W202–W208 (2009)

    Article  CAS  Google Scholar 

  34. Huang, D. W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4, 44–57 (2009)

    Article  CAS  Google Scholar 

  35. Das, R., Laederach, A., Pearlman, S. M., Herschlag, D. & Altman, R. B. SAFA: semi-automated footprinting analysis software for high-throughput quantification of nucleic acid footprinting experiments. RNA 11, 344–354 (2005)

    Article  CAS  Google Scholar 

  36. Deigan, K. E., Li, T. W., Mathews, D. H. & Weeks, K. M. Accurate SHAPE-directed RNA structure determination. Proc. Natl Acad. Sci. USA 106, 97–102 (2009)

    Article  ADS  CAS  Google Scholar 

  37. Zuker, M. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 31, 3406–3415 (2003)

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by US Veterans Affairs Office of Research and Development funding to P.A.K. and National Institutes of Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases) grant AR49737 to P.A.K., and by NIH R01-HG004361 and California Institute for Regenerative Medicine to H.Y.C. H.Y.C. is an Early Career Scientist of the Howard Hughes Medical Institute.

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Authors

Contributions

M.K. designed and executed experiments, analysed data and wrote the manuscript. D.E.W., Z.S., C.C., A.Z., C.S.L., R.J.F., K.Q., J.C., D.J., G.X.Y.Z., G.E.K., A.F.G., R.C.S., R.A.F. and S.A. executed experiments, analysed data and contributed to design of experimentation. A.R. and J.L.R. helped design experiments and analysed data. P.A.K. and H.Y.C. designed experiments, analysed data and wrote the manuscript.

Corresponding authors

Correspondence to Howard Y. Chang or Paul A. Khavari.

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The authors declare no competing financial interests.

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Kretz, M., Siprashvili, Z., Chu, C. et al. Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature 493, 231–235 (2013). https://doi.org/10.1038/nature11661

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