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The mechanism underlying the “unified model” of YTHDF proteins

ABSTRACT: The mechanism underlying the “unified model” of YTHDF proteins

PROVIDER: PRJNA828181 | ENA |

REPOSITORIES: ENA

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A unified model for the function of YTHDF proteins in the regulation of m6A-modified mRNA

Project description:N6-methyladenosine (m6A) is the most abundant mRNA nucleotide modification and regulates critical aspects of cellular physiology and differentiation. m6A is thought to mediate its effects through a complex network of interactions between different m6A sites and three functionally distinct cytoplasmic YTHDF m6A-binding proteins (DF1, DF2, and DF3). In contrast to the prevailing model, we show that DF proteins bind the same m6A-modified mRNAs, rather than different mRNAs. Furthermore, we find that DF proteins do not induce translation in HeLa cells. Instead, the DF paralogs act redundantly to mediate mRNA degradation and cellular differentiation. The ability of DF proteins to regulate stability and differentiation becomes evident only when all three DF paralogs are simultaneously depleted. Our studies reveal a unified model of m6A function in which all m6A-modified mRNAs are subjected to the combined action of the YTHDF proteins in proportion to the number of m6A sites.

2020-06-02 | GSE134380 | GEO

The mechanism underlying the “unified model” of YTHDF proteins

Project description:The YTH N6-methyladenosine RNA Binding Proteins (YTHDFs) mediate the functions of N6-methyladenosine (m6A) in RNA. Recently, a report proposed that all YTHDFs work redundantly to facilitate RNA decay, raising questions about the exact functions of individual YTHDFs, especially YTHDF1 and YTHDF2. We show that YTHDF1 and YTHDF2 differ in their low-complexity domains (LCDs), and this causes different behaviors in condensate formation and subsequent physiological functions. Biologically, we find that the global stabilization of RNA after depletion of all YTHDFs is a result of increased P-body formation and is independent of mRNA m6A methylation.

2023-01-12 | GSE201070 | GEO

A unified model for the function of YTHDF proteins in the regulation of m6A-modified mRNA

Project description:A unified model for the function of YTHDF proteins in the regulation of m6A-modified mRNA

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Dynamic O-GlcNAcylation of YTHDF proteins controls translation of m6A-modified mRNA

Project description:N6-methyladenosine (m6A) is the most abundant internal mRNA nucleotide modification in mammals, regulating critical aspects of cell physiology and differentiation. The YTHDF proteins are the primary readers of m6A modifications and exert physiological functions of m6A in the cytosol. Elucidating the regulatory mechanisms of YTHDF proteins is critical to understanding m6A biology. Here, we report a mechanism that protein post-translational modifications control the biological functions of the YTHDF proteins. We find that YTHDF1 and YTHDF3, but not YTHDF2, carry high levels of nutrient-sensing O-GlcNAc modifications. O-GlcNAc modification attenuates the translation promoting function of YTHDF1 and YTHDF3 by blocking their interactions with proteins associated with mRNA translation. We further demonstrate that O-GlcNAc modifications on YTHDF1 and YTHDF2 regulate the assembly, stability, and disassembly of stress granule, facilitating rapid exchange of m6A-modified mRNAs in stress granules for recovery from stress. Therefore, our results discover an important regulatory pathway of YTHDF functions, adding an additional layer of complexity to the post-transcriptional regulation function of mRNA m6A.

2023-08-31 | GSE216570 | GEO

Single-molecule analysis of RNA:protein interactions reveals sequential binding of different YTHDF proteins to the same mRNA molecules [TRIBE_STAMP]

Project description:N6-methyladenosine (m6A) plays critical roles in gene expression control by recruiting the cytoplasmic reader proteins YTHDF1,2 and 3. Recently, the function of YTHDF proteins and whether they bind to shared or distinct sets of methylated mRNAs in cells has been the subject of debate. Here, we developed TRIBE-STAMP, an approach for single-molecule detection of the target RNAs of two RNA binding proteins simultaneously in cells. Applying TRIBE-STAMP to the YTHDF proteins revealed that most target mRNAs are shared among the three YTHDF proteins. Surprisingly, we also found that individual mRNA molecules can be bound by more than one YTHDF protein throughout their lifetime. Furthermore, we show that YTHDF proteins bind sequentially to target methylated mRNAs, with YTHDF1 binding before YTHDF2 or YTHDF3. Our data reveal shared molecular interactions among the YTHDF proteins and support a model in which YTHDF1 and YTHDF3 are unlikely to promote rapid mRNA decay.

2022-10-28 | GSE200712 | GEO

Single-molecule analysis of RNA:protein interactions reveals sequential binding of different YTHDF proteins to the same mRNA molecules [Polysome]

2022-10-28 | GSE201538 | GEO

Single-molecule analysis of RNA:protein interactions reveals sequential binding of different YTHDF proteins to the same mRNA molecules [RIP-Seq]

2022-10-28 | GSE201540 | GEO

m6A and YTHDF proteins control the subcellular localization of select neuronal mRNAs

Project description:m6A and YTHDF proteins control the subcellular localization of select neuronal mRNAs

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Dynamic O-GlcNAcylation of YTHDF proteins controls translation of m6A-modified mRNA

Project description:Dynamic O-GlcNAcylation of YTHDF proteins controls translation of m6A-modified mRNA

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Single-molecule identification of the target RNAs of different RNA binding proteins simultaneously in cells