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RNA-seq and ribosome profiling of heat shocked wild type and Mettl14 -/- mouse embryonic stem cells

ABSTRACT: N6-methyladenosine (m6A) is a dynamic and reversible nucleotide modification in mRNA. m6A alters mRNA fate, but it is unclear why the effects of m6A can vary in different cellular contexts. Here we show that methylated mRNAs are catalysts for liquid-liquid phase separation of the YTHDF family of m6A-binding proteins. RNAs that contain multiple, but not single, m6A residues recruit multiple YTHDF proteins, causing them to undergo a proximity-induced phase separation. YTHDF proteins show liquid-like properties upon binding polymethylated mRNAs in cells, and partition into endogenous phase-separated compartments, such as P-bodies, neuronal RNA granules, and stress granules. The complexes of YTHDF proteins and polymethylated mRNAs are targeted to different compartments depending on the cell context, leading to different effects on m6A mRNAs. These studies reveal a role for nucleotide modifications in regulating phase separation and indicate that the cellular properties of m6A-modified mRNAs can be explained by liquid-liquid phase separation principles.

ORGANISM(S): Mus musculus

PROVIDER: GSE125725 | GEO | 2019/07/15

REPOSITORIES: GEO

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Ribosome profiling on heat shocked wild type and Mettl14 -/- mES cells

Project description:Abstract : "A hallmark of the cellular response to environmental stress is the formation of stress granules. Stress granules are RNA-protein assemblies that provide an adaptive response to stress; however, the basis for their formation and how they contribute to the stress response remains incompletely understood. Here we show that the mRNA modification N6-methyladenosine (m6A) is a mark that targets mRNAs to stress granules. We find that m6A mRNAs are highly enriched in stress granules, and this is mediated by m6A-induced liquid-liquid phase separation of the YTHDF family of m6A-binding proteins. These proteins bind poly-methylated m6A mRNAs, causing them to form liquid droplets that partition into stress granules. Moreover, disrupting either m6A or YTHDF proteins prevents stress granule formation." The goal of this experiment is to understand how recruitment of m6A mRNA to stress granules influences the translational response to heat shock. Result: we found that m6A-containing mRNA are preferentially repressed during stress, and that m6A is required for translational recovery after heat shock

2021-01-15 | GSE109253 | GEO

RNA-seq of arsenite-induced stress granule transcriptomes in control and Mettl3- and m6A-depleted mouse embryonic fibroblasts (MEFs)

Project description:N6-methyladenosine (m6A) is the most abundant nucleotide modification found on mRNA. m6A has been previously shown to facilitate recruitment of mRNAs to stress granules due to interactions between m6A and the YTHDF proteins. Although protein-RNA interactions are known to contribute to the recruitment of mRNAs to stress granules, the predominant driver of mRNA recruitment to stress granules is thought to be RNA-RNA interactions between long RNAs. Here, we show that m6A contributes significantly to the length-dependent effect of mRNA enrichment in stress granules and that upon depletion of METTL3, the enzyme responsible for adding m6A to nascent transcripts, the nature of the stress granule transcriptome is fundamentally altered by greatly reducing the propensity of long mRNAs to enter stress granules. This reveals that not only does m6A enhance the phase separation of mRNAs, but that it is a driving force underpinning length-dependent enrichment of mRNAs in stress granules.

2023-06-01 | GSE190121 | GEO

METTL3-mediated chromatin contacts promote phase separation during senescence [fastGro-seq]

Project description:Cellular senescence is a stable state of growth arrest that emerges as a response to stress. The methyltransferase complex (MTC) has been shown to facilitate the expression of the senescence-associated secretion phenotype (SASP) factors via genome-wide redistribution. However, whether and how MTC impacts on the three-dimensional (3D) chromatin organization and its functional implications during senescence remain largely unknown. Here we show that the MTC complex coordinates its enzymatic activity-dependent and -independent functions to enforce cellular senescence. Specifically, METTL3-mediated chromatin loops induce Hexokinase 2 (HK2) expression during senescence. The elevated HK2 expression subsequently promotes liquid-liquid phase separation (LLPS), manifesting as stress granules. These phase-separated stress granules act as reservoirs to sequester cell-cycle related mRNAs harboring polymethylated m6A sites, impeding their efficient translation. Overall, we uncover a mechanism by which senescent cells utilize phase-separated stress granules, facilitated by MTC-mediated HK2 activation, to sequester cell-cycle related mRNAs in governing senescence-associated stable growth arrest.

2024-04-22 | GSE243046 | GEO

METTL3-mediated chromatin contacts promote phase separation during senescence [Mettl3-HiChIP-seq]

2024-04-22 | GSE243044 | GEO

METTL3-mediated chromatin contacts promote phase separation during senescence [H3K27Ac-HiChIP-seq]

2024-04-22 | GSE243043 | GEO

METTL3-mediated chromatin contacts promote phase separation during senescence [KAS-seq]

2024-04-22 | GSE243042 | GEO

L-bodies are novel RNA-protein condensates driving RNA transport in Xenopus oocytes

Project description:RNP granules are membrane-less compartments within cells, formed by phase separation, that function as regulatory hubs for diverse biological processes. However, the mechanisms by which RNAs and proteins interact to promote RNP granule assembly and function in vivo remain unclear. In Xenopus laevis oocytes, maternal mRNAs are transported as large RNPs to the vegetal hemisphere of the developing oocyte, where local translation is critical for proper embryonic patterning. Here, we demonstrate that vegetal transport RNPs represent a new class of cytoplasmic RNP granule, termed Localization-bodies (L-bodies). We show that L-bodies are multiphase RNP granules, containing a dynamic liquid-like protein-containing phase surrounding a non-dynamic RNA-containing substructure. Our results support a role for RNA as a critical scaffold component within these RNP granules and suggest that cis-elements within localized mRNAs may drive subcellular RNA localization through control over phase behavior.

2020-09-20 | GSE158246 | GEO

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

YTHDF3 facilitates translation and decay of the N6-methyladenosine-modified RNA

Project description:N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), and plays important roles in cell differentiation and organism development. It regulates multiple steps throughout the RNA life cycle including RNA processing, translation, and metabolism, via the recognition by selective binding proteins. In cytoplasm, m6A binding protein YTHDF1 facilitates translation of m6A-modified mRNAs, and YTHDF2 accelerates the decay of m6A-modified transcripts. The biological function of YTHDF3, another cytoplasmic m6A binder of the YTH domain family, remains unknown. Here, we report that YTHDF3 promotes protein synthesis in synergy with YTHDF1, and affects methylated mRNA decay mediated by YTHDF2. Cells deficient in all of YTHDF proteins experience the most dramatic accumulation of the m6A-methylated transcripts. These results indicate that in cytoplasm, YTHDF proteins act in an integrated and cooperative network to accelerate metabolism of m6A-modified mRNAs. The combinative and dynamic nature of YTHDF proteins may collectively impact fundamental biological processes and diseases related to m6A RNA methylation.

2016-09-15 | GSE86214 | GEO

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

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