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.

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