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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Accessions

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.

Author information

Author notes

    • Zurab Siprashvili
    • , Ci Chu
    •  & Dan E. Webster

    These authors contributed equally to this work.

Affiliations

  1. The Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, 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, Pennsylvania 19104, USA

    • Subhadra Aiyer
    •  & Arjun Raj
  3. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • John L. Rinn
  4. Howard Hughes Medical Institute, Stanford, California 94305, USA

    • Howard Y. Chang
  5. Veterans Affairs Palo Alto Healthcare System, Palo Alto, California 94304, 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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

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    Supplementary Information

    This file contains Supplementary Figures 1-7 and Supplementary Tables 1-8.

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DOI

https://doi.org/10.1038/nature11661

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