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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
Summary
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.
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