Zc3h13 Regulates Nuclear RNA m6A Methylation and Mouse Embryonic Stem Cell Self-Renewal

Mol Cell. 2018 Mar 15;69(6):1028-1038.e6. doi: 10.1016/j.molcel.2018.02.015.


N6-methyladenosine (m6A) is an abundant modification in eukaryotic mRNA, regulating mRNA dynamics by influencing mRNA stability, splicing, export, and translation. However, the precise m6A regulating machinery still remains incompletely understood. Here we demonstrate that ZC3H13, a zinc-finger protein, plays an important role in modulating RNA m6A methylation in the nucleus. We show that knockdown of Zc3h13 in mouse embryonic stem cell significantly decreases global m6A level on mRNA. Upon Zc3h13 knockdown, a great majority of WTAP, Virilizer, and Hakai translocate to the cytoplasm, suggesting that Zc3h13 is required for nuclear localization of the Zc3h13-WTAP-Virilizer-Hakai complex, which is important for RNA m6A methylation. Finally, Zc3h13 depletion, as does WTAP, Virilizer, or Hakai, impairs self-renewal and triggers mESC differentiation. Taken together, our findings demonstrate that Zc3h13 plays a critical role in anchoring WTAP, Virilizer, and Hakai in the nucleus to facilitate m6A methylation and to regulate mESC self-renewal.

Keywords: Zc3h13; m(6)A; mESC self-renewal; nuclear localization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Active Transport, Cell Nucleus
  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cell Differentiation
  • Cell Nucleus / metabolism*
  • Cell Proliferation*
  • Cell Self Renewal*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Humans
  • Methylation
  • Mice
  • Mouse Embryonic Stem Cells / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • RNA Processing, Post-Transcriptional*
  • RNA Splicing Factors
  • RNA Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins
  • Signal Transduction
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism


  • 3' Untranslated Regions
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • RNA Splicing Factors
  • RNA, Messenger
  • RNA-Binding Proteins
  • Wtap protein, mouse
  • Zc3h13 protein, mouse
  • N-methyladenosine
  • Ubiquitin-Protein Ligases
  • Adenosine