The N6‐methyladenosine mRNA methylase METTL14 promotes renal ischemic reperfusion injury via suppressing YAP1

Xu, Yao−Zhong; Yuan, Xiao; Wu, Jia; Chen, Ruo Yang; Lei, Xia; Zhang, Ming; Han, Cong; Mou, Shan

doi:10.1002/jcb.29258

Cited by 54 publications

(45 citation statements)

References 23 publications

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“…This suggests that METTL14 has an important regulatory role in m 6 A modification. Moreover, recent studies have shown that METTL14 plays vital roles in the regulation of m 6 A modification in target mRNAs in various biological processes, such as microRNA processing, viral-associated tumorigenesis, stem cell differentiation, and renal ischemic reperfusion 38 - 41 . When the m 6 A information of mRNA is 'written', further recognition requires the 'reader' proteins.…”

Section: Discussionmentioning

confidence: 99%

METTL14 aggravates endothelial inflammation and atherosclerosis by increasing FOXO1 N6-methyladeosine modifications

et al. 2020

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Aims: The N6-methyladenosine (m 6 A) modification plays an important role in various biological processes, but its role in atherosclerosis remains unknown. The aim of this study was to investigate the role and mechanism of m 6 A modification in endothelial cell inflammation and its influence on atherosclerosis development. Methods: We constructed a stable TNF-α-induced endothelial cell inflammation model and assessed the changes in the expression of m 6 A modification-related proteins to identify the major factors involved in this process. The m 6 A-modified mRNAs were identified by methylated RNA immunoprecipitation (RIP) sequencing and forkhead box O1 (FOXO1) was selected as a potential target. Through cytological experiments, we verified whether methyltransferase-like 14 (METTL14) regulates FOXO1 expression by regulating m 6 A-dependent mRNA and protein interaction. The effect of METTL14 on atherosclerosis development in vivo was verified using METTL14 knockout mice. Results: These findings confirmed that METTL14 plays major roles in TNF-α-induced endothelial cell inflammation. During endothelial inflammation, m 6 A modification of FOXO1, an important transcription factor, was remarkably increased. Moreover, METTL14 knockdown significantly decreased TNF-α-induced FOXO1 expression. RIP assay confirmed that METTL14 directly binds to FOXO1 mRNA, increases its m 6 A modification, and enhances its translation through subsequent YTH N6-methyladenosine RNA binding protein 1 recognition. Furthermore, METTL14 was shown to interact with FOXO1 and act directly on the promoter regions of VCAM-1 and ICAM-1 to promote their transcription, thus mediating endothelial cell inflammatory response. In vivo experiments showed that METTL14 gene knockout significantly reduced the development of atherosclerotic plaques. Conclusion: METTL14 promotes FOXO1 expression by enhancing its m 6 A modification and inducing endothelial cell inflammatory response as well as atherosclerotic plaque formation. Decreased expression of METTL14 can inhibit endothelial inflammation and atherosclerosis development. Therefore, METTL14 may serve as a potential target for the clinical treatment of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

METTL14 aggravates endothelial inflammation and atherosclerosis by increasing FOXO1 N6-methyladeosine modifications

et al. 2020

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“…It was reported that mice with YAP1 gene mutation died about 10 days of embryonic stage(10). Existing studies have shown that YAP1 is widely involved in the development of various organs or tissues, including skin(24), kidney(25), lung(26), skeletal muscle(27), etc.. However, the role of YAP1 in periodontitis has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Role of YAP1 gene in proliferation and osteogenic differentiation of human periodontal ligament stem cells induced by TNF-α

Dong

Sun

2020

Preprint

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Background ： Periodontitis is a chronic inflammatory disease that occurs in periodontal tissues and can cause tooth loosening and loss in severe cases. As the main effector of downstream of Hippo signaling pathway, Yes-related protein 1 (YAP1) plays an important role in cell proliferation and differentiation. However, the role of YAP1 in periodontitis has not been reported. Methods: Cell activity was detected by CCk-8. YAP1 was overexpressed by cell transfection, and then RT-qPCR and western blot were used to detect the expression of YAP1. The cell proliferation was determined by clone formation assay, and the expression of proliferation-related proteins was determined by western blot. The cell differentiation was detected by Elisa kit of ALP and alizarin red staining. Finally, western blot was used to detect the expression of differentiation-related protein and Hippo signaling pathway-related proteins. Results: With the increase of concentration induced by TNF-α, the cell survival rate of human periodontal ligament stem cells (HPDLSC) decreased significantly. After the overexpression of YAP1, cell proliferation and proliferation-related protein expression increased. Overexpression of YAP1 can improve the differentiation and the formation of osteoblasts of HPDLSCs induced by TNF-α. The expression of Hippo signaling pathway-related proteins transcriptional coactivators with PDZ binding domains (TAZ), TEA domain family member (TRED)increased and proliferation-related protein P27 decreased. Conclusion: TNF-α can inhibit proliferation and osteogenic differentiation of HPDLSCs, which can be ameliorated by the YAP1 gene through the Hippo signaling pathway. Our paper suggested that YAP1 may be a potential therapeutic target for periodontitis.

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“…YAP1 mRNA methylation levels were reduced in HK-2 cells with METTL14 knockdown and in the kidney from METTL14 knockout mice. Loss of METTL14 function resulted in decreased YAP1 methylation levels and increased YAP1 protein translation 109 . Inhibition of the YAP1-TEAD pathway by peptide 17 eliminated the protective effect of METTL14 on renal I/R in vivo and in vitro, indicating that the role of METTL14 in renal I/R is dependent on the activation of YAP1 and the YAP1-TEAD pathway by RNA methylation 109 .…”

Section: Epigenetic Regulations In Ischemia-reperfusion Injurymentioning

confidence: 99%

“…Loss of METTL14 function resulted in decreased YAP1 methylation levels and increased YAP1 protein translation 109 . Inhibition of the YAP1-TEAD pathway by peptide 17 eliminated the protective effect of METTL14 on renal I/R in vivo and in vitro, indicating that the role of METTL14 in renal I/R is dependent on the activation of YAP1 and the YAP1-TEAD pathway by RNA methylation 109 . This suggests that the regulation of m 6 A RNA methylation is involved in the development and progression of renal I/R injury.…”

Section: Epigenetic Regulations In Ischemia-reperfusion Injurymentioning

confidence: 99%

N6-methyladenosine (m6A) methylation in ischemia–reperfusion injury

Yao

Han

et al. 2020

Cell Death Dis

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Ischemia-reperfusion (I/R) injury is common during surgery and often results in organ dysfunction. The mechanisms of I/R injury are complex, diverse, and not well understood. RNA methylation is a novel epigenetic modification that is involved in the regulation of various biological processes, such as immunity, response to DNA damage, tumorigenesis, metastasis, stem cell renewal, fat differentiation, circadian rhythms, cell development and differentiation, and cell division. Research on RNA modifications, specifically N6-methyladenosine (m 6 A), have confirmed that they are involved in the regulation of organ I/R injury. In this review, we summarized current understanding of the regulatory roles and significance of m 6 A RNA methylation in I/R injury in different organs.

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The N6‐methyladenosine mRNA methylase METTL14 promotes renal ischemic reperfusion injury via suppressing YAP1

Cited by 54 publications

References 23 publications

METTL14 aggravates endothelial inflammation and atherosclerosis by increasing FOXO1 N6-methyladeosine modifications

METTL14 aggravates endothelial inflammation and atherosclerosis by increasing FOXO1 N6-methyladeosine modifications

Role of YAP1 gene in proliferation and osteogenic differentiation of human periodontal ligament stem cells induced by TNF-α

N6-methyladenosine (m6A) methylation in ischemia–reperfusion injury

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