METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA

Wu, Zeming; Shi, Yue; Lu, Mingming; Song, Moshi; Yu, Zihui; Wang, Jilu; Wang, Si; Ren, Jie; Yang, Yun‐Gui; Liu, Guanghui; Zhang, Weiqi; Ci, Weimin; Qu, Jing

doi:10.1093/nar/gkaa816

Cited by 118 publications

(109 citation statements)

References 85 publications

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“…METTL3 knockdown and m 6 A depletion could limit self-renewal and promote cell differentiation in epiblast stem cells while improving pluripotency, block regeneration in embryonic stem cells [ 13 , 26 , 34 ]. A recent study suggested METTL3 knockout accelerated mesenchymal stem cell senescence by modulating m 6 A modification of MIS12 which supported our data [ 35 ]. In our study, METTL3 inhibition in immature DPSCs promoted cell senescence and apoptosis which might further result in reduced regenerative potential in mature teeth.…”

Section: Discussionsupporting

confidence: 92%

METTL3-mediated m6A modification regulates cell cycle progression of dental pulp stem cells

Liu

Zhang

et al. 2021

Stem Cell Res Ther

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Background Dental pulp stem cells (DPSCs) are a promising cell source in endodontic regeneration and tissue engineering with limited self-renewal and pluripotency capacity. N6-methyladenosine (m6A) is the most prevalent, reversible internal modification in RNAs associated with stem cell fate determination. In this study, we aim to explore the biological effect of m6A methylation in DPSCs. Methods m6A immunoprecipitation with deep sequencing (m6A RIP-seq) demonstrated the features of m6A modifications in DPSC transcriptome. Lentiviral vectors were constructed to knockdown or overexpress methyltransferase like 3 (METTL3). Cell morphology, viability, senescence, and apoptosis were analyzed by β-galactosidase, TUNEL staining, and flow cytometry. Bioinformatic analysis combing m6A RIP and shMETTL3 RNA-seq functionally enriched overlapped genes and screened target of METTL3. Cell cycle distributions were assayed by flow cytometry, and m6A RIP-qPCR was used to confirm METTL3-mediated m6A methylation. Results Here, m6A peak distribution, binding area, and motif in DPSCs were first revealed by m6A RIP-seq. We also found a relatively high expression level of METTL3 in immature DPSCs with superior regenerative potential and METTL3 knockdown induced cell apoptosis and senescence. A conjoint analysis of m6A RIP and RNA sequencing showed METTL3 depletion associated with cell cycle, mitosis, and alteration of METTL3 resulted in cell cycle arrest. Furthermore, the protein interaction network of differentially expressed genes identified Polo-like kinase 1 (PLK1), a critical cycle modulator, as the target of METTL3-mediated m6A methylation in DPSCs. Conclusions These results revealed m6A methylated hallmarks in DPSCs and a regulatory role of METTL3 in cell cycle control. Our study shed light on therapeutic approaches in vital pulp therapy and served new insight into stem cell-based tissue engineering.

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Section: Discussionsupporting

confidence: 92%

METTL3-mediated m6A modification regulates cell cycle progression of dental pulp stem cells

Liu

Zhang

et al. 2021

Stem Cell Res Ther

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“…Library preparation and sequencing were performed as previously reported ( 53 ). Briefly, total RNAs were extracted using TRIzol Reagent, genomic DNAs were removed using the DNA-free Kit and mRNAs were purified by Poly (A) enrichment.…”

Section: Methodsmentioning

confidence: 99%

SIRT3 consolidates heterochromatin and counteracts senescence

Diao

et al. 2021

Nucleic Acids Research

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Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase linked to a broad range of physiological and pathological processes, including aging and aging-related diseases. However, the role of SIRT3 in regulating human stem cell homeostasis remains unclear. Here we found that SIRT3 expression was downregulated in senescent human mesenchymal stem cells (hMSCs). CRISPR/Cas9-mediated depletion of SIRT3 led to compromised nuclear integrity, loss of heterochromatin and accelerated senescence in hMSCs. Further analysis indicated that SIRT3 interacted with nuclear envelope proteins and heterochromatin-associated proteins. SIRT3 deficiency resulted in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, increased chromatin accessibility and aberrant repetitive sequence transcription. The re-introduction of SIRT3 rescued the disorganized heterochromatin and the senescence phenotypes. Taken together, our study reveals a novel role for SIRT3 in stabilizing heterochromatin and counteracting hMSC senescence, providing new potential therapeutic targets to ameliorate aging-related diseases.

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“…Previous studies have discussed the mechanism of m6A-promoted cell senescence ( Li Q. et al, 2017 ; Wu et al, 2020 ). The METTL3/METTL14-mediated m6A methylation can enhance p21 expression which is further promoted.…”

Section: Discussionmentioning

confidence: 99%

“…oxidative stress-induced cellular senescence ( Li Q. et al, 2017 ). Through interacting with Lamin A, METTL3/14 can be properly localized in the nuclear speckles to achieve the regulatory function ( Wu et al, 2020 ). Our study has deepened the current understanding of m6A modification in cell senescence.…”

Section: Discussionmentioning

confidence: 99%

N6-Methyladenosine Induced miR-34a-5p Promotes TNF-α-Induced Nucleus Pulposus Cell Senescence by Targeting SIRT1

Zhu

Sun

Zhu

et al. 2021

Front. Cell Dev. Biol.

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Low back pain is tightly associated with intervertebral disc degeneration (IVDD) and aberrant nucleus pulposus (NP) is a critical cause. miRNAs N6-methyladenosine (m6A) modification accounts for the TNF-α-induced senescence of NP cells. The aim of this study was to investigate whether m6A modification regulates TNF-α-mediated cell viability, cell cycle arrest, and cell senescence and how it works. The results showed that METTL14 expression positively correlated with m6A and TNF-α expression in HNPCs. The knockdown of METTL14 led to the inhibition of the TNF-α-induced cell senescence. METTL14 overexpression promoted cell senescence. METTL14 regulated the m6A modification of miR-34a-5p and interacted with DGCR8 to process miR-34a-5p. The miR-34a-5p inhibitor inhibited the cell cycle senescence of HNPCs. miR-34a-5p was predicted to interact with the SIRT1 mRNA. SIRT1 overexpression counteracted the miR-34a-5p-promoted cell senescence. METTL14 participates in the TNF-α-induced m6A modification of miR-34a-5p to promote cell senescence in HNPCs and NP cells of IVDD patients. Downregulation of either METTL14 expression or miR-34a-5p leads to the inhibition of cell cycle arrest and senescence. SIRT1 mRNA is an effective binding target of miR-34a-5p, and SIRT1 overexpression mitigates the cell cycle arrest and senescence caused by miR-34a-5p.

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METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA

Cited by 118 publications

References 85 publications

METTL3-mediated m6A modification regulates cell cycle progression of dental pulp stem cells

METTL3-mediated m6A modification regulates cell cycle progression of dental pulp stem cells

SIRT3 consolidates heterochromatin and counteracts senescence

N6-Methyladenosine Induced miR-34a-5p Promotes TNF-α-Induced Nucleus Pulposus Cell Senescence by Targeting SIRT1

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