Context-dependent functional compensation between Ythdf m6A reader proteins

Lior Lasman, Vladislav Krupalnik, Sergey Viukov, Nofar Mor, Alejandro Aguilera-Castrejon, Dan Schneir, Jonathan Bayerl, Orel Mizrahi, Shani Peles, Shadi Tawil, Shashank Sathe, Aharon Nachshon, Tom Shani, Mirie Zerbib, Itay Kilimnik, Stefan Aigner, Archana Shankar, Jasmine R Mueller, Schraga Schwartz, Noam Stern-GinossarGene W Yeo, Shay Geula, Noa Novershtern, Jacob H Hanna

Research output: Contribution to journalArticlepeer-review


The N6-methyladenosine (m6A) modification is the most prevalent post-transcriptional mRNA modification, regulating mRNA decay and splicing. It plays a major role during normal development, differentiation, and disease progression. The modification is regulated by a set of writer, eraser, and reader proteins. The YTH domain family of proteins, consists of three homologous m6A-binding proteins, Ythdf1, Ythdf2, and Ythdf3, which were suggested to have different cellular functions. However, their sequence similarity and their tendency to bind the same targets suggest that they may have overlapping roles. We systematically knocked out (KO) the Mettl3 writer, each of the Ythdf readers, and the three readers together (triple-KO). We then estimated the effect in vivo in mouse gametogenesis, postnatal viability, and in vitro in mouse embryonic stem cells (mESCs). In gametogenesis, Mettl3-KO severity is increased as the deletion occurs earlier in the process, and Ythdf2 has a dominant role that cannot be compensated by Ythdf1 or Ythdf3, due to differences in readers' expression pattern across different cell types, both in quantity and in spatial location. Knocking out the three readers together and systematically testing viable offspring genotypes revealed a redundancy in the readers' role during early development that is Ythdf1/2/3 gene dosage-dependent. Finally, in mESCs there is compensation between the three Ythdf reader proteins, since the resistance to differentiate and the significant effect on mRNA decay occur only in the triple-KO cells and not in the single KOs. Thus, we suggest a new model for the Ythdf readers function, in which there is profound dosage-dependent redundancy when all three readers are equivalently coexpressed in the same cell types.

Original languageEnglish
Pages (from-to)1373-1391
Number of pages19
JournalGenes and Development
Issue number19-20
Early online date17 Sep 2020
StatePublished - 1 Oct 2020

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology


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