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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / metabolism*
  • Cell Differentiation
  • Cell Line
  • Cytosine / metabolism
  • DNA Methylation*
  • Epidermal Cells / cytology*
  • Epidermal Cells / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Human Embryonic Stem Cells / cytology
  • Humans
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • RNA / genetics
  • RNA / metabolism*
  • Vault Ribonucleoprotein Particles / genetics*
  • Vault Ribonucleoprotein Particles / metabolism


  • Vault Ribonucleoprotein Particles
  • RNA
  • 5-Methylcytosine
  • Cytosine
  • Methyltransferases