Loss of 5-methylcytosine alters the biogenesis of vault-derived small RNAs to coordinate epidermal differentiation

  • Nat Commun. 2019 Jun 11;10(1):2550. doi: 10.1038/s41467-019-10020-7.
Abdulrahim A Sajini  1  2  3 ,  Nila Roy Choudhury  4 ,  Rebecca E Wagner  1 ,  Susanne Bornelöv  5 ,  Tommaso Selmi  1 ,  Christos Spanos  6 ,  Sabine Dietmann  5 ,  Juri Rappsilber  6  7 ,  Gracjan Michlewski  8  9  10 ,  Michaela Frye  11  12
Affiliations
  • 1. Department of Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK.
  • 2. Department of Biomedical Engineering, Khalifa University of Science and Technology, P.O. Box 127788, Abu Dhabi, United Arab Emirates.
  • 3. Department of Medical Laboratory Technology, University of Tabuk, Tabuk, P.O. Box 71491, Saudi Arabia.
  • 4. Division of Infection and Pathway Medicine, University of Edinburgh, The Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
  • 5. Wellcome MRC Cambridge Stem Cell Institute, Tennis Court Road, Cambridge, CB2 1QR, UK.
  • 6. Wellcome Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh, EH9 3BF, UK.
  • 7. Department of Biotechnology, Technische Universität Berlin, Gustav-Meyer-Allee 25, 13355, Berlin, Germany.
  • 8. Division of Infection and Pathway Medicine, University of Edinburgh, The Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK. [email protected].
  • 9. Wellcome Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh, EH9 3BF, UK. [email protected].
  • 10. ZJU-UoE Institute, Zhejiang University, 718 East Haizhou Road, Haining, Zhejiang, 314400, P.R. China. [email protected].
  • 11. Department of Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK. [email protected].
  • 12. German Cancer Research Centre (Deutsches Krebsforschungszentrum, DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. [email protected].
PMID: 31186410 DOI: 10.1038/s41467-019-10020-7
Abstract

The presence and absence of RNA modifications regulates RNA metabolism by modulating the binding of writer, reader, and eraser proteins. For 5-methylcytosine (m5C) however, it is largely unknown how it recruits or repels RNA-binding proteins. Here, we decipher the consequences of m5C deposition into the abundant non-coding vault RNA VTRNA1.1. Methylation of Cytosine 69 in VTRNA1.1 occurs frequently in human cells, is exclusively mediated by NSUN2, and determines the processing of VTRNA1.1 into small-vault RNAs (svRNAs). We identify the serine/arginine rich splicing factor 2 (SRSF2) as a novel VTRNA1.1-binding protein that counteracts VTRNA1.1 processing by binding the non-methylated form with higher affinity. Both NSUN2 and SRSF2 orchestrate the production of distinct svRNAs. Finally, we discover a functional role of svRNAs in regulating the epidermal differentiation programme. Thus, our data reveal a direct role for m5C in the processing of VTRNA1.1 that involves SRSF2 and is crucial for efficient cellular differentiation.