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Epitranscriptomic program promotes skeletal stem cell quiescence and pluripotency by regulating proteostasis via METTL3-FEM1B-GLI1 axis

ABSTRACT: Epitranscriptomic program promotes skeletal stem cell quiescence and pluripotency by regulating proteostasis via METTL3-FEM1B-GLI1 axis

PROVIDER: PRJNA1198024 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31709100_1.fastq.gz	Fastqsanger.gz
	SRR31709100_2.fastq.gz	Fastqsanger.gz
	SRR31709101_1.fastq.gz	Fastqsanger.gz
	SRR31709101_2.fastq.gz	Fastqsanger.gz
	SRR31709102_1.fastq.gz	Fastqsanger.gz

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Epitranscriptomic program promotes skeletal stem cell quiescence and pluripotency by regulating proteostasis via METTL3-FEM1B-GLI1 axis

Project description:Skeletal stem cells (SSCs) maintain the hierarchy of skeletal system via pluripotency and differentiation capacity. However, it remains largely unknown how these cells adapt its highly nutrient-deficient niche and precisely regulate their function to keep this skeletal hierarchical organization. Here, we delineate a comprehensive m6A landscape across skeletal hierarchy, and identify a new epitranscriptomic program to promote SSCs quiescence and potency by regulating proteostasis via METTL3-FEM1B-GLI1 axis. We find m6A modifications arise mostly from skeletal stem cells (SSCs) in stem-progenitor population and play critical roles in cell fate maintenance and transformation in skeletal hierarchy. Genetic deletion of Mettl3 in skeletal stem and progenitors impairs bone development with shortened limbs, disturbs growth plate, and decreases bone mass. Moreover, Mettl3 loss induces quiescence loss, and damages the self-renewal ability, and differentiation ability of SSCs. Mechanistically, Mettl3-mediated m6A modification reduces mRNA stability of a Cul2-RING E3 ligase complex substrate-recognition subunit Fem1b, which subsequently influences proteostasis of SSCs and stabilizes Gli1 protein, a key transcription factor of Hedgehog pathway for maintaining SSC identity and function. Thus, our findings present a fascinating portrait of m6A modification of skeletal hierarchy and reveal the essential role of an epitranscriptome-proteostasis axis in maintaining SSC function.

2024-12-18 | GSE284224 | GEO

An epitranscriptomic program maintains skeletal stem cell quiescence via a METTL3-FEM1B-GLI1 axis

Project description:Skeletal stem cells (SSCs) maintain the skeletal system via pluripotency and differentiation capacity. However, it remains largely unknown how these cells precisely regulate their function to maintain skeletal organization. Here, we delineate the m6A RNA modification landscape across skeletal cell populations in the mouse epiphysis. Our findings show that m6A modifications are prevalent in skeletal stem cell and progenitor populations and play critical roles in cell fate determination. Genetic deletion of Mettl3, the core catalytic subunit of the N6-methyltransferase complex, in murine skeletal stem and progenitors impaired bone development, leading to shortened limbs, disrupted growth plate zonation, and decreased bone mass. Moreover, Mettl3 deficiency induced quiescence exit in SSCs, together with compromised self-renewal capacity and differentiation potential. Mechanistically, Mettl3-mediated m6A modification reduced mRNA stability of the Cul2-RING E3 ligase complex subunit Fem1b, which subsequently stabilizes Gli1 protein, a key transcription factor of Hedgehog pathway for maintaining SSC identity and function. Thus, we present a comprehensive RNA m6A modification landscape of skeletal cell hierarchy and uncover the essential function of epitranscriptomically-regulated proteostasis in maintaining SSCs quiescence and potency.

| S-SCDT-10_1038-S44318-025-00399-Z | biostudies-other

Murine kidneys： WT Models vs METTL3-cKO Models

Project description:MeRIP and RNA Epitranscriptomic Microarray analysis in kidneys of conditional knockout (cKO) METTL3 mice and wild type mice following glyoxylate-induced CaOx nephrocalcinosis.In METTL3-cKO mice, METTL3 subjected the specific absence from renal tubular epithelial cells. Goal was to determine the effects of METTL3 gene knockout on the expression and N6-methyladenosine (m6A) modifications of global gene.

2025-09-05 | GSE212868 | GEO

Converged Epitranscriptomic Co-regulation of TGFβ Signaling Components Suppresses the Quiescence Transition of Early Postnatal Hippocampal Neural Stem Cells

Project description:Quiescence acquisition of proliferating neural stem cells (NSCs) is required to establish the adult NSC pool yet the underlying molecular mechanisms are not well-understood. Here we showed that conditional deletion of the m6A reader Ythdf2, which promotes mRNA decay, in proliferating NSCs in the early postnatal mouse hippocampus led to elevated quiescence acquisition with decreased neurogenesis. Multimodal profiling of m6A modification, YTHDF2 binding, and mRNA decay in hippocampal NSCs identified shared targets in multiple TGFβ signaling pathway components, including TGFβ ligands, maturation factors, receptors, transcription regulators, and signaling regulators. Functionally, Ythdf2 deletion led to TGFβ signaling activation in NSCs, suppression of which rescued elevated quiescence acquisition of proliferating hippocampal NSCs. Our study reveals the dynamic nature and critical roles of mRNA decay in establishing the quiescent adult hippocampal NSC pool and uncovers a novel mode of epitranscriptomic control via co-regulation of multiple components of the same signaling pathway.

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Targeted Quantitative Profiling of Epitranscriptomic Reader, Writer and Eraser Proteins Revealed Potential Crosstalk between N6-Methyladenosine and Other RNA Modifications

Project description:N⁶-methyladenosine (m6A) and its reader, writer, and eraser (RWE) proteins assume crucial roles in regulating the splicing, stability, and translation of mRNA. To our knowledge, no systematic investigations have been conducted about the crosstalk between m6A and other modified nucleosides in RNA. Herein, we modified our recently established liquid chromatography-parallel-reaction monitoring (LC-PRM) method by incorporating stable isotope-labeled (SIL) peptides as internal or surrogate standards for profiling epitranscriptomic RWE proteins. We were able to detect reproducibly a total of 114 RWE proteins in HEK293T cells with the genes encoding m6A eraser proteins (i.e., ALKBH5, FTO) and the catalytic subunit of the major m6A writer complex (i.e., METTL3) being individually ablated. Notably, eight proteins were altered by more than 1.5-fold in the opposite directions in HEK293T cells depleted of METTL3 and ALKBH5. Analysis of published m6A mapping results revealed the presence of m6A in the corresponding mRNAs of four of these proteins. Together, we integrated SIL peptides into our LC-PRM method for quantifying epitranscriptomic RWE proteins, and our work revealed potential crosstalks between m6A and other epitranscriptomic modifications. Our modified LC-PRM method with the use of SIL peptides should be applicable for high-throughput profiling of epitranscriptomic RWE proteins in other cell types and in tissues.

2022-09-24 | PXD036032 | Pride

Stage-specific requirement for Mettl3-dependent m6A epitranscriptomic regulation during myogenesis [RNA-Seq]

Project description:Stage-specific requirement for Mettl3-dependent m6A epitranscriptomic regulation during myogenesis [RNA-Seq]

| PRJNA1243358 | ENA

Stage-specific requirement for Mettl3-dependent m6A epitranscriptomic regulation during myogenesis [meRIP-Seq]

Project description:Stage-specific requirement for Mettl3-dependent m6A epitranscriptomic regulation during myogenesis [meRIP-Seq]

| PRJNA1243359 | ENA

Stage-specific requirement for Mettl3-dependent m6A epitranscriptomic regulation during myogenesis [RNA-Seq]

Project description:The role of N6-methyladenosine (m6A) in muscle formation and maintenance remains incompletely understood, particularly with respect to the contribution of methyltransferase-like 3 (METTL3), the core component of the methyltransferase complex (MTC), to myogenesis. Here, we show the involvement of METTL3 in the m6A epitranscriptome during myogenesis. Our findings reveal a correlation between METTL3-regulated m6A modifications and myoblast fusion during differentiation and regeneration. We observed significant upregulation of METTL3 following injury and identified numerous alterations in myogenic pathways. Furthermore, we detected differential patterns of METTL3-regulated m6A modifications in genes during differentiation, with some genes exhibiting loss and others showing gain. Our study revealed that the fusion factors Mymx and Mymk are downstream elements of METTL3 involved in myogenesis, and both exhibit upregulated expression and m6A levels during myogenesis. Our findings provide valuable resources for elucidating the function and mechanism of METTL3-regulated m6A modifications in myogenesis, thereby revealing the regulatory role of METTL3 in myoblast fusion.

2025-09-03 | GSE293208 | GEO

Stage-specific requirement for Mettl3-dependent m6A epitranscriptomic regulation during myogenesis [meRIP-Seq]

2025-09-03 | GSE293212 | GEO

METTL3 promotes translation in human cancer cells

Project description:we find METTL3 associates with polyribosomes and promotes translation. METTL3 depletion inhibits translation, and both wild-type and catalytically inactive METTL3 promote translation when tethered to the 3' untranslated region (UTR) of a reporter mRNA. Mechanistically, METTL3 enhances mRNA translation through an interaction with the translation initiation machinery. m6A seq in A549 and H1299 cells, RNA seq in METTL3 knockdown cells

2016-07-03 | E-GEOD-76367 | biostudies-arrayexpress

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