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A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA

Sara Zaccara1, Samie R Jaffrey1

  • 1Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA.

Cell
|June 4, 2020
PubMed

Insights

N6-methyladenosine (m6A) RNA modification regulates cell differentiation. YTHDF proteins, previously thought to bind different mRNAs, actually bind the same ones, mediating mRNA degradation and differentiation redundantly.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • RNA Biology

Background:

  • N6-methyladenosine (m6A) is the most prevalent mRNA modification.
  • m6A regulates cellular physiology and differentiation.
  • Cytoplasmic YTHDF m6A-binding proteins (DF1, DF2, DF3) are key mediators.

Purpose of the Study:

  • To investigate the binding interactions of YTHDF proteins with m6A-modified mRNAs.
  • To elucidate the functional roles of YTHDF proteins in mRNA regulation and cellular differentiation.
  • To challenge and refine the prevailing model of m6A function.

Main Methods:

  • Analysis of YTHDF protein binding to m6A-modified mRNAs.
  • Functional assays in HeLa cells to assess mRNA translation and degradation.
  • Depletion studies of DF paralogs to evaluate their combined effects.

Main Results:

  • YTHDF proteins bind the same m6A-modified mRNAs, contrary to previous models.
  • YTHDF proteins do not induce translation in HeLa cells.
  • DF paralogs act redundantly to mediate mRNA degradation and cellular differentiation, with effects evident only upon simultaneous depletion.
  • A unified model where YTHDF proteins act collectively on m6A mRNAs.

Conclusions:

  • The YTHDF proteins function redundantly to regulate mRNA stability and cellular differentiation.
  • Simultaneous depletion of all three YTHDF paralogs is necessary to observe their full impact.
  • This study proposes a unified model for m6A RNA regulation by YTHDF proteins.
Keywords:
translation, mRNA stability, m(6)A, METTL3, YTHDF1, YTHDF2, YTHDF3, CLIP, RNA-binding

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