Loss of m6A methyltransferase METTL3 promotes heart regeneration and repair after myocardial injury

Gong, Rui; Wang, Xiuxiu; Li, Hanjing; Liu, Shenzhen; Jiang, Zhao-Peng; Zhao, Yiming; Ye, Yu; Han, Zhenbo; Yu, Ying; Dong, Chaorun; Li, Shuainan; Xu, Binbin; Zhang, Wenwen; Wang, Ning; Li, Xingda; Gao, Xinlu; Yang, Fan; Bamba, Djibril; Ma, Wanbiao; Liu, Yu; Cai, Benzhi

doi:10.1016/j.phrs.2021.105845

Cited by 56 publications

(48 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… Dorn et al (2019) showed that N6 adenosine methylation regulated by METTL3 is crucial for hypertrophy’s pathological process in vivo and in vitro . Loss of METTL3 enhanced heart regeneration and repair after myocardial injury ( Gong et al, 2021 ). Nonetheless, the roles of m6A regulators in MI remained largely unclear.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators Expression Identify Distinct Molecular Subtypes of Myocardial Infarction

Shi

Cao

Zhang

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Background: Myocardial infarction (MI) is one of the leading threats to human health. N6-methyladenosine (m6A) modification, as a pivotal regulator of messenger RNA stability, protein expression, and cellular processes, exhibits important roles in the development of cardiac remodeling and cardiomyocyte contractile function.Methods: The expression levels of m6A regulators were analyzed using the GSE5406 database. We analyzed genome-wide association study data and single-cell sequencing data to confirm the functional importance of m6A regulators in MI. Three molecular subtypes with different clinical characteristics were established to tailor treatment strategies for patients with MI. We applied pathway analysis and differentially expressed gene (DEG) analysis to study the changes in gene expression and identified four common DEGs. Furthermore, we constructed the protein–protein interaction network and confirmed several hub genes in three clusters of MI. To lucubrate the potential functions, we performed a ClueGO analysis of these hub networks.Results: In this study, we identified that the levels of FTO, YTHDF3, ZC3H13, and WTAP were dramatically differently expressed in MI tissues compared with controls. Bioinformatics analysis showed that DEGs in MI were significantly related to modulating calcium signaling and chemokine signaling, and m6A regulators were related to regulating glucose measurement and elevated blood glucose levels. Furthermore, genome-wide association study data analysis showed that WTAP single-nucleotide polymorphism was significantly related to the progression of MI. In addition, single-cell sequencing found that WTAP is widely expressed in the heart tissues. Moreover, we conducted consensus clustering for MI in view of the dysregulated m6A regulators’ expression in MI. According to the expression levels, we found MI patients could be clustered into three subtypes. Pathway analysis showed the DEGs among different clusters in MI were assigned to HIF-1, IL-17, MAPK, PI3K-Akt signaling pathways, etc. The module analysis detected several genes, including BAG2, BAG3, MMP2, etc. We also found that MI-related network was significantly related to positive and negative regulation of angiogenesis and response to heat. The hub networks in MI clusters were significantly related to antigen processing and ubiquitin-mediated proteolysis, RNA splicing, and stability, indicating that these processes may contribute to the development of MI.Conclusion: Collectively, our study could provide more information for understanding the roles of m6A in MI, which may provide a novel insight into identifying biomarkers for MI treatment and diagnosis.

show abstract

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators Expression Identify Distinct Molecular Subtypes of Myocardial Infarction

Shi

Cao

Zhang

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Also, the further investigation reported METTL3 decreased TFEB expression via methylating TFEB at two m 6 A residues and promoting the interaction between NRNPD with TFEB pre-mRNA(Song et al, 2019). Also, the functional role of METTL3 in MI has been reported by other groups Gong et al (2021). revealed that silencing of METTL3 improved cardiac function of the damaged heart that exposure to MI via promoting CMs proliferation.…”

mentioning

confidence: 64%

“…Also, the functional role of METTL3 in MI has been reported by other groups. Gong et al (2021) revealed that silencing of METTL3 improved cardiac function of the damaged heart that exposure to MI via promoting CMs proliferation. Mechanistically, METTL3 deficiency decreased the m 6 A modification of pri‐miR‐143, suppressing pri‐miR‐143 into mature miR‐143‐3p, thereby resulting in a reduced level of miR‐143‐3p.…”

Section: “Writers” In Heart‐related Diseasesmentioning

confidence: 99%

“…More interestingly, METTL3 +/− mice exhibited a reduced scar size after MI, thereby evaluating cardiac functions after MI upon METTL3 knockdown. In summary, METTL3 plays a crucial role in regulating post-MI cardiac function(Gong et al, 2021).Lastly, the m 6 A modification also acts as an important regulator in activation of cardiac fibroblasts. T Li et al (2021).…”

mentioning

confidence: 92%

See 1 more Smart Citation

Emerging role of m⁶A modification in cardiovascular diseases

Peng

Long

Feili

et al. 2022

Cell Biology International

View full text Add to dashboard Cite

Cardiovascular diseases (CVDs) contribute to the leading cause of death worldwide. Despite significant improvements in CVDs diagnosis and treatment, a continued effort to explore novel therapeutic strategies is urgently need. N6‐methyladenosine (m6A) RNA methylation, well known as the most prevalent type of RNA modifications, involved in RNA stability, nuclear exports, translation, and decoy, plays a crucial role in the pathogenesis of a variety of diseases, including CVDs, cancer, and drug resistance. Here, our article summarizes cellular functions of m6A modulators and recent research progress concerning the functions and mechanisms of m6A methylation in CVDs, in hope of providing references for exploring novel therapeutic approaches and potential biomarkers in the treatment of CVDs.

show abstract

“…To promote endogenous cardiomyocyte proliferation, initial approaches targeted universal cell cycle regulators such as cyclins, cyclin-dependent kinases (CDKs), tumor suppressor genes, and cell-intrinsic signaling pathways that regulate cardiomyocytes proliferation during development (7,10). These include mainly developmental transcription factors comprising the Hippo, Hedgehog (HH), Wnt pathway, HIF1α, SMADs, TBX20, p53, Jarid2, GATA4, MEIS1/2, Retinoblastoma, PITX2, E2F family members, KLF1, REST (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) as well as chromatin remodeling proteins (26), and microRNAs (miR-590, miR-199a, miR-548c, miR-509, miR-23b, miR-17-92 cluster, miR302-367, miR-143) (27)(28)(29)(30). Recently, induced expression of the pluripotency factors OCT4, SOX2, KLF4, AND C-MYC (OSKM) was shown to trigger cardiomyocyte dedifferentiation by reprogramming cardiomyocytes to a fetal-like regenerative state.…”

Section: Introductionmentioning

confidence: 99%

Tailoring Cardiac Synthetic Transcriptional Modulation Towards Precision Medicine

Schoger

Panàkovà

Zelarayán

2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Molecular and genetic differences between individual cells within tissues underlie cellular heterogeneities defining organ physiology and function in homeostasis as well as in disease states. Transcriptional control of endogenous gene expression has been intensively studied for decades. Thanks to a fast-developing field of single cell genomics, we are facing an unprecedented leap in information available pertaining organ biology offering a comprehensive overview. The single-cell technologies that arose aided in resolving the precise cellular composition of many organ systems in the past years. Importantly, when applied to diseased tissues, the novel approaches have been immensely improving our understanding of the underlying pathophysiology of common human diseases. With this information, precise prediction of regulatory elements controlling gene expression upon perturbations in a given cell type or a specific context will be realistic. Simultaneously, the technological advances in CRISPR-mediated regulation of gene transcription as well as their application in the context of epigenome modulation, have opened up novel avenues for targeted therapy and personalized medicine. Here, we discuss the fast-paced advancements during the recent years and the applications thereof in the context of cardiac biology and common cardiac disease. The combination of single cell technologies and the deep knowledge of fundamental biology of the diseased heart together with the CRISPR-mediated modulation of gene regulatory networks will be instrumental in tailoring the right strategies for personalized and precision medicine in the near future. In this review, we provide a brief overview of how single cell transcriptomics has advanced our knowledge and paved the way for emerging CRISPR/Cas9-technologies in clinical applications in cardiac biomedicine.

show abstract

Loss of m6A methyltransferase METTL3 promotes heart regeneration and repair after myocardial injury

Cited by 56 publications

References 53 publications

Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators Expression Identify Distinct Molecular Subtypes of Myocardial Infarction

Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators Expression Identify Distinct Molecular Subtypes of Myocardial Infarction

Emerging role of m⁶A modification in cardiovascular diseases

Tailoring Cardiac Synthetic Transcriptional Modulation Towards Precision Medicine

Contact Info

Product

Resources

About

Loss of m6A methyltransferase METTL3 promotes heart regeneration and repair after myocardial injury

Cited by 56 publications

References 53 publications

Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators Expression Identify Distinct Molecular Subtypes of Myocardial Infarction

Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators Expression Identify Distinct Molecular Subtypes of Myocardial Infarction

Emerging role of m6A modification in cardiovascular diseases

Tailoring Cardiac Synthetic Transcriptional Modulation Towards Precision Medicine

Contact Info

Product

Resources

About

Emerging role of m⁶A modification in cardiovascular diseases