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

Nature volume 493, pages 231–235 (2013)Cite this article

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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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Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

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

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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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Author notes

  1. Zurab Siprashvili, Ci Chu and Dan E. Webster: These authors contributed equally to this work.

Authors and Affiliations

  1. The Program in Epithelial Biology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Markus Kretz, Zurab Siprashvili, Ci Chu, Dan E. Webster, Ashley Zehnder, Kun Qu, Carolyn S. Lee, Ross J. Flockhart, Abigail F. Groff, Jennifer Chow, Danielle Johnston, Grace E. Kim, Robert C. Spitale, Ryan A. Flynn, Grace X. Y. Zheng, Howard Y. Chang & Paul A. Khavari

  2. Department of Bioengineering, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Subhadra Aiyer & Arjun Raj

  3. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, 02138, Massachusetts, USA

    John L. Rinn

  4. Howard Hughes Medical Institute, Stanford, 94305, California, USA

    Howard Y. Chang

  5. Veterans Affairs Palo Alto Healthcare System, Palo Alto, 94304, California, USA

    Paul A. Khavari

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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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