Mettl3-mediated m6A modification of Fgf16 restricts cardiomyocyte proliferation during heart regeneration

Jiang, Fu-Qing; Liu, Kun; Chen, Jiaxuan; Cao, Yan; Chen, Wu-Yun; Zhao, Wan-Ling; Song, Guohua; Liang, Chi-Qian; Zhou, Yi-Min; Huang, Huanlei; Huang, Ruijin; Zhao, Hui; Park, Kyu Sang; Ju, Zhenyu; Cai, Dongqing; Qi, Xufeng

doi:10.7554/elife.77014

Cited by 15 publications

(6 citation statements)

References 64 publications

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“…Contrary to Kun Zhao et al, studies have shown that transfection of small interfering RNA targeting METTL3 can promote CMs proliferation, while overexpression of METTL3 has the opposite effect . Moreover, METTL3 overexpression decreased cardiomyocyte proliferation and suppressed heart regeneration in postnatal mice . The above-mentioned studies highlight the different roles of METTL3 in different pathological processes and at different time points.…”

Section: Resultsmentioning

confidence: 85%

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Programmed Release METTL3-14 Inhibitor Microneedle Protects Myocardial Function by Reducing Drp1 m6A Modification-Mediated Mitochondrial Fission

Huang,

Xie,

et al. 2023

ACS Appl. Mater. Interfaces

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M6A modification is an RNA-important processing event mediated by methyltransferases METTL3 and METTL14 and the demethylases. M6A dynamic changes after myocardial infarction (MI), involved in the massive loss of cardiomyocytes due to hypoxia, as well as the recruitment and activation of myofibroblasts. Balanced mitochondrial fusion and fission are essential to maintain intracardiac homeostasis and reduce poststress myocardial remodeling. Double-layer programmed drug release microneedle (DPDMN) breaks the limitations of existing therapeutic interventions in one period or one type of cells, and multitargeted cellular combination has more potential in MI therapy. By employing hypoxia-ischemic and TGF-β1-induced fibrosis cell models, we found that METTL3-14 inhibition effectively decreased cardiomyocyte death through the reduction of mitochondrial fragmentation and inhibiting myofibrillar transformation. DPDMN treatment of MI in rat models showed improved cardiac function and decreased infarct size and fibrosis level, demonstrating its superior effectiveness. The DPDMN delivers METTL3 inhibitor swiftly in the early phase to rescue dying cardiomyocytes and slowly in the late phase to achieve long-term suppression of fibroblast over proliferation, collagen synthesis, and deposition. RIP assay and mechanistic investigation confirmed that METTL3 inhibition reduced the translation efficiency of Drp1 mRNA by 5′UTR m6A modification, thus decreasing the Drp1 protein level and mitochondrial fragment after hypoxic-ischemic injury. This project investigated the efficacy of DPDMNs-loaded METTL3 inhibitor in MI treatment and the downstream signaling pathway proteins, providing an experimental foundation for the translation of the utility, safety, and versatility of microneedle drug delivery for MI into clinical applications.

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Section: Resultsmentioning

confidence: 85%

“…35 Moreover, METTL3 overexpression decreased cardiomyocyte proliferation and suppressed heart regeneration in postnatal mice. 36 The above-mentioned studies highlight the different roles of METTL3 in different pathological processes and at different time points.…”

Section: Characterization Of Dpdmnsmentioning

confidence: 99%

Programmed Release METTL3-14 Inhibitor Microneedle Protects Myocardial Function by Reducing Drp1 m6A Modification-Mediated Mitochondrial Fission

Huang,

Xie,

et al. 2023

ACS Appl. Mater. Interfaces

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“…Gong et al showed that loss of METTL3 promoted cardiomyocytes cell cycle re-entered, infract size decreased and cardiac function improved after myocardial infarction by reducing primary miR-143 m 6 A modification [ 28 ]. Similarly, Jiang et al revealed that Mettl3 deficiency obviously increased cardiomyocyte proliferation and facilitated heart regeneration following heart injury in neonatal and adult mice [ 29 ]. On the contrary, Zhao et al .…”

Section: Discussionmentioning

confidence: 99%

The roles of METTL3 on autophagy and proliferation of vascular smooth muscle cells are mediated by mTOR rather than by CDK1

Luo

Huo

et al. 2023

Cell Div

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Background Aberrant proliferation of vascular smooth muscle cells (VSMCs) is the cause of neointima formation followed by vascular injury. Autophagy is involved in this pathological process, but its function is controversial. Recently, we found that methyltransferase like 3 (METTL3) inhibited VSMC proliferation by activating autophagosome formation. Moreover, we also demonstrated that METTL3 reduced the levels of phosphorylated mammalian target of rapamycin (p-mTOR) and cyclin dependent kinase 1 (p-CDK1/CDC2), which were critical for autophagy and proliferation regulation. However, whether mTOR and CDK1 mediated the function of METTL3 on autophagy and proliferation in VSMCs remains unknown. Results We showed that the activator of mTOR, MHY1485 largely reversed the effects of METTL3 overexpression on VSMC autophagy and proliferation. Rapamycin, the inhibitor of mTOR, obviously nullified the pro-proliferation effects of METTL3 knockdown by activating autophagy in VSMCs. Unexpectedly, mTOR did not contribute to the impacts of METTL3 on migration and phenotypic switching of VSMCs. On the other hand, by knockdown of CDK1 in VSMC with METTL3 deficiency, we demonstrated that CDK1 was involved in METTL3-regulated proliferation of VSMCs, but this effect was not mediated by autophagy. Conclusions We concluded that mTOR but not CDK1 mediated the role of METTL3 on VSMC proliferation and autophagy.

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“…METTL3 is a pivotal catalytic subunit in the methyltransferase complex. Its expression increases in the postnatal mouse heart and following neonatal heart injury but does not change after MI-induced injury in the adult heart [50]. The overexpression of METTL3 suppresses the proliferation of primary CMs isolated from neonatal mice and inhibits cardiac regeneration in vivo, whereas the knockdown of METTL3 increases CM proliferation and promotes cardiac regeneration after MI-induced heart injury in neonatal, postnatal, and adult mice [50,51].…”

Section: Ythdf2 Mediates the Activity Of Mettl3 To Prevent Excessive ...mentioning

confidence: 99%

RNA-Binding Proteins as Critical Post-Transcriptional Regulators of Cardiac Regeneration

Shi

2023

IJMS

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Myocardial injury causes death to cardiomyocytes and leads to heart failure. The adult mammalian heart has very limited regenerative capacity. However, the heart from early postnatal mammals and from adult lower vertebrates can fully regenerate after apical resection or myocardial infarction. Thus, it is of particular interest to decipher the mechanism underlying cardiac regeneration that preserves heart structure and function. RNA-binding proteins, as key regulators of post-transcriptional gene expression to coordinate cell differentiation and maintain tissue homeostasis, display dynamic expression in fetal and adult hearts. Accumulating evidence has demonstrated their importance for the survival and proliferation of cardiomyocytes following neonatal and postnatal cardiac injury. Functional studies suggest that RNA-binding proteins relay damage-stimulated cell extrinsic or intrinsic signals to regulate heart regenerative capacity by reprogramming multiple molecular and cellular processes, such as global protein synthesis, metabolic changes, hypertrophic growth, and cellular plasticity. Since manipulating the activity of RNA-binding proteins can improve the formation of new cardiomyocytes and extend the window of the cardiac regenerative capacity in mammals, they are potential targets of therapeutic interventions for cardiovascular disease. This review discusses our evolving understanding of RNA-binding proteins in regulating cardiac repair and regeneration, with the aim to identify important open questions that merit further investigations.

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Mettl3-mediated m6A modification of Fgf16 restricts cardiomyocyte proliferation during heart regeneration

Cited by 15 publications

References 64 publications

Programmed Release METTL3-14 Inhibitor Microneedle Protects Myocardial Function by Reducing Drp1 m6A Modification-Mediated Mitochondrial Fission

Programmed Release METTL3-14 Inhibitor Microneedle Protects Myocardial Function by Reducing Drp1 m6A Modification-Mediated Mitochondrial Fission

The roles of METTL3 on autophagy and proliferation of vascular smooth muscle cells are mediated by mTOR rather than by CDK1

RNA-Binding Proteins as Critical Post-Transcriptional Regulators of Cardiac Regeneration

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