Roles of N6-Methyladenosine (m6A) in Stem Cell Fate Decisions and Early Embryonic Development in Mammals

Zhang, Meng; Zhai, Yanhui; Zhang, Sheng; Dai, Xiangpeng; Li, Ziyi

doi:10.3389/fcell.2020.00782

Cited by 61 publications

(68 citation statements)

References 126 publications

(246 reference statements)

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“…This decrease was reversed by blocking FTO overexpression in the cultured spinal neurons co-transduced with AAV5- Fto shRNA ( Figure 6I ). Given the role of m 6 A modification in mRNA translation ( Jia et al, 2019 ; Zhang M. et al, 2020 ; Zhang Z. et al, 2020 ; Liu et al, 2020 ; Song et al, 2020 ), the evidence described above indicates that FTO likely erased the m 6 A enrichment in Mmp24 mRNA to promote the translation of Mmp24 mRNA in the spinal cord neurons under neuropathic pain condition.…”

Section: Resultsmentioning

confidence: 99%

MMP24 Contributes to Neuropathic Pain in an FTO-Dependent Manner in the Spinal Cord Neurons

Huang

Zhang

et al. 2021

Front. Pharmacol.

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Nerve injury-induced gene expression change in the spinal cord is critical for neuropathic pain genesis. RNA N6-methyladenosine (m6A) modification represents an additional layer of gene regulation. We showed that spinal nerve ligation (SNL) upregulated the expression of matrix metallopeptidase 24 (MMP24) protein, but not Mmp24 mRNA, in the spinal cord neurons. Blocking the SNL-induced upregulation of spinal MMP24 attenuated local neuron sensitization, neuropathic pain development and maintenance. Conversely, mimicking MMP24 increase promoted the spinal ERK activation and produced evoked nociceptive hypersensitivity. Methylated RNA Immunoprecipitation Sequencing (MeRIP-seq) and RNA Immunoprecipitation (RIP) assay indicated the decreased m6A enrichment in the Mmp24 mRNA under neuropathic pain condition. Moreover, fat-mass and obesity-associated protein (FTO) was colocalized with MMP24 in spinal neurons and shown increased binding to the Mmp24 mRNA in the spinal cord after SNL. Overexpression or suppression of FTO correlates with promotion or inhibition of MMP24 expression in cultured spinal cord neurons. In conclusion, SNL promoted the m6A eraser FTO binding to the Mmp24 mRNA, which subsequently facilitated the translation of MMP24 in the spinal cord, and ultimately contributed to neuropathic pain genesis.

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Section: Resultsmentioning

confidence: 99%

MMP24 Contributes to Neuropathic Pain in an FTO-Dependent Manner in the Spinal Cord Neurons

Huang

Zhang

et al. 2021

Front. Pharmacol.

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“…Identifying factors involved in the osteogenic differentiation of ASCs is important for better understanding the mechanism of osteogenic differentiation. Recent studies have shown that m 6 A modification plays essential roles in stem cell fate decisions in a stage-, state-, and cell type-specific manner [ 26 , 36 – 40 ]. In the case of osteogenic differentiation, reduced m 6 A level in BMSCs inhibited osteogenic differentiation by affecting the PTH/Pth1r signaling axis, the PI3K-AKT signaling pathways, or the alternative splicing of VEGFA [ 30 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome-wide m6A methylome during osteogenic differentiation of human adipose-derived stem cells

et al. 2021

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Objectives Adipose-derived stem cells are frequently used for bone regeneration both in vitro and in vivo. N6-methyladenosine (m6A) is the most abundant post-transcriptional modification on eukaryotic RNAs and plays multifaceted roles in development and diseases. However, the regulatory mechanisms of m6A in osteogenic differentiation of human adipose-derived stem cells (hASCs) remain elusive. The present study aimed to build the transcriptome-wide m6A methylome during the osteogenic differentiation of hASCs. Materials and methods hASCs were harvested after being cultured in a basic or osteogenic medium for 7 days, and the osteogenic differentiation was validated by alkaline phosphatase (ALP) and Alizarin Red S staining, ALP activity assay, and qRT-PCR analysis of ALP, RUNX2, BGLAP, SPP1, SP7, and COL1A1 genes. The m6A level was colorimetrically measured, and the expression of m6A regulators was confirmed by qRT-PCR and western blot. Moreover, m6A MeRIP-seq and RNA-seq were performed to build the transcriptome and m6A methylome. Furthermore, bioinformatic analyses including volcano plots, Venn plots, clustering analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, gene sets enrichment analysis, and protein-protein interaction analysis were conducted. Results In total, 1145 differentially methylated peaks, 2261 differentially expressed genes, and 671 differentially methylated and expressed genes (DMEGs) were identified. GO and KEGG pathway analyses conducted for these DMEGs revealed extensive and osteogenic biological functions. The “PI3K-Akt signaling pathway”; “MAPK signaling pathway”; “parathyroid hormone synthesis, secretion, and action”; and “p53 signaling pathway” were significantly enriched, and the DMEGs in these pathways were identified as m6A-specific key genes. A protein-protein interaction network based on DMEGs was built, and VEGFA, CD44, MMP2, HGF, and SPARC were speculated as the hub DMEGs. Conclusions The total m6A level was reduced with osteogenic differentiation of hASCs. The transcriptome-wide m6A methylome built in the present study indicated quite a few signaling pathways, and hub genes were influenced by m6A modification. Future studies based on these epigenetic clues could promote understanding of the mechanisms of osteogenic differentiation of hASCs.

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“…The role of RNA modifications in the context of developmental and neurological disorders remains an active area of study. m 6 A has been previously found to play important roles in embryonic development and neurobiological functions [ 84 , 85 ]. The roles of m 6 A and other RNA modifications in mediating neurologic function are further discussed elsewhere [ 84 , 86 , 87 , 88 , 89 ].…”

Section: Rna Modifications In Diseasesmentioning

confidence: 99%

Context-Dependent Roles of RNA Modifications in Stress Responses and Diseases

Wilkinson

Cui

2021

IJMS

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RNA modifications are diverse post-transcriptional modifications that regulate RNA metabolism and gene expression. RNA modifications, and the writers, erasers, and readers that catalyze these modifications, serve as important signaling machineries in cellular stress responses and disease pathogenesis. In response to stress, RNA modifications are mobilized to activate or inhibit the signaling pathways that combat stresses, including oxidative stress, hypoxia, therapeutic stress, metabolic stress, heat shock, DNA damage, and ER stress. The role of RNA modifications in response to these cellular stressors is context- and cell-type-dependent. Due to their pervasive roles in cell biology, RNA modifications have been implicated in the pathogenesis of different diseases, including cancer, neurologic and developmental disorders and diseases, and metabolic diseases. In this review, we aim to summarize the roles of RNA modifications in molecular and cellular stress responses and diseases.

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Roles of N6-Methyladenosine (m6A) in Stem Cell Fate Decisions and Early Embryonic Development in Mammals

Cited by 61 publications

References 126 publications

MMP24 Contributes to Neuropathic Pain in an FTO-Dependent Manner in the Spinal Cord Neurons

MMP24 Contributes to Neuropathic Pain in an FTO-Dependent Manner in the Spinal Cord Neurons

Transcriptome-wide m6A methylome during osteogenic differentiation of human adipose-derived stem cells

Context-Dependent Roles of RNA Modifications in Stress Responses and Diseases

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