4.7 Article

METTL14 suppresses pyroptosis and diabetic cardiomyopathy by downregulating TINCR lncRNA

Journal

CELL DEATH & DISEASE
Volume 13, Issue 1, Pages -

Publisher

SPRINGERNATURE
DOI: 10.1038/s41419-021-04484-z

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Funding

  1. National Natural Science Foundation of China [82000252, 81900345]
  2. Project From Health Department of Zhejiang Provincial [2021RC032]
  3. Medical and Health Science and Technology Plan Project of Shaoxing City [2020A13018]

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This study reveals the important role of METTL14-mediated m6A methylation and lncRNA regulation in pyroptosis and DCM. The results show that METTL14 suppresses pyroptosis and DCM by downregulating lncRNA TINCR, and the underlying mechanisms involve m6A methylation and RNA degradation.
N6-methyladenosine (m6A) is one of the most important epigenetic regulation of RNAs, such as lncRNAs. However, the underlying regulatory mechanism of m6A in diabetic cardiomyopathy (DCM) is very limited. In this study, we sought to define the role of METTL14-mediated m6A modification in pyroptosis and DCM progression. DCM rat model was established and qRT-PCR, western blot, and immunohistochemistry (IHC) were used to detect the expression of METTL14 and TINCR. Gain-and-loss functional experiments were performed to define the role of METTL14-TINCR-NLRP3 axis in pyroptosis and DCM. RNA pulldown and RNA immunoprecipitation (RIP) assays were carried out to verify the underlying interaction. Our results showed that pyroptosis was tightly involved in DCM progression. METTL14 was downregulated in cardiomyocytes and hear tissues of DCM rat tissues. Functionally, METTL14 suppressed pyroptosis and DCM via downregulating lncRNA TINCR, which further decreased the expression of key pyroptosis-related protein, NLRP3. Mechanistically, METTL14 increased m6A methylation level of TINCR gene, resulting in its downregulation. Moreover, the m6A reader protein YTHDF2 was essential for m6A methylation and mediated the degradation of TINCR. Finally, TINCR positively regulated NLRP3 by increasing its mRNA stability. To conclude, our work revealed the novel role of METTL14-mediated m6A methylation and lncRNA regulation in pyroptosis and DCM, which could help extend our understanding the epigenetic regulation of pyroptosis in DCM progression.

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