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Cited by 243RNA modifications and cancerRNA regulation and diseaseRNA Research and Splicing

Context-dependent functional compensation between Ythdf m6A reader proteins

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Lasman, Lior, Krupalnik, Vladislav, Viukov, Sergey, Mor, Nofar, Aguilera-Castrejon, Alejandro, Schneir, Dan, Bayerl, Jonathan, Mizrahi, Orel +16 more·2020·Genes & Development
DOI 10.1101/gad.340695.120PMC PMC7528697
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Abstract

The N6-methyladenosine (m 6 A) 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 m 6 A-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.

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Authors
Lasman, L., Krupalnik, V., Viukov, S., Mor, N., Aguilera-Castrejon, A., Schneir, D., Bayerl, J., Mizrahi, O., Peles, S., Tawil, S., Sathe, S., Nachshon, A., Shani, T., Zerbib, M., Kilimnik, I., Aigner, S., Shankar, A., Mueller, J. R., Schwartz, S., Stern-Ginossar, N., Yeo, G. W., Geula, S., Novershtern, N., & Hanna, J. H.
Affiliations
  • Weizmann Institute of Science (IL)
  • University of California San Diego (US)
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2020-09-17
Volume
34
Issue
19-20
Pages
1373-1391
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.340695.120
PMC
PMC7528697
OpenAlex
W3087500438
Cited by
243
References
8
Citations by year
2026: 24 · 2025: 33 · 2024: 36 · 2023: 55 · 2022: 44 · 2021: 46 · 2020: 4 · 2014: 1
Type
posted content
Language
en
Open access
Licence
cc-by-nc
Locations
  • Genes & Development (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • Nella and Leon Benoziyo Center for Neurological Diseases
  • David and Fela Shapell Family Center for Genetic Disorders Research
  • Kekst Family Institute for Medical Genetics
  • Helen and Martin Kimmel Institute for Stem Cell Research
  • Flight Attendant Medical Research Council
  • Dr. Barry Sherman Center for Medicinal Chemistry
  • Pascal and Ilana Mantoux
  • Dr. Beth Rom-Rymer Stem Cell Research Fund
  • Edmond de Rothschild Foundations
  • Zantker Charitable Foundation
  • estate of Zvia Zeroni
  • European Research Council
  • Israel Science Foundation
  • Minerva
  • Israel Cancer Research Fund
  • the BSF
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
N6-methyladenosine, m6A reader proteins, YTHDF1, YTHDF2, YTHDF3, METTL3, functional redundancy, gene dosage compensation, gametogenesis, mouse embryonic stem cells, mRNA degradation
MeSH terms
Animals, Cell Line, Dosage Compensation, Genetic, Fertility, Gametogenesis, Methyltransferases, RNA-Binding Proteins, Gene Deletion, Mice, Knockout, Gene Expression Regulation, Developmental, Gene Expression Profiling, Mice, Embryonic Stem Cells

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