Fibroblast-specific knockout of METTL1 attenuates myocardial infarction-induced cardiac fibrosis

Wang, Liang; Zhou, Jiamin; Kong, Li; Ying, Guoqiu; Sha, Juan; Yi, Dasong; Zeng, Junyi; Xiong, Wenjun; Wen, Tong-Chun

doi:10.1016/j.lfs.2023.121926

Cited by 8 publications

(2 citation statements)

References 27 publications

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“…Wang et al . showed that METTL1 ablation in fibroblasts decreases the expression of m7G methylated fibrotic genes, thereby alleviating myocardial infarction-induced cardiac fibrosis [ 25 ]. The Nudix superfamily, a series of hydrolases that possess a conserved nucleoside diphosphate linked to another moiety X (Nudix), serving as divalent cation-regulated enzymes that hydrolyze various dinucleotides and inositol pyrophosphates (PP-InsPs), contains 8 of 22 Nudix proteins in the human genome, namely, Nudt2, Nudt3, Nudt12, Nudt15, Nudt16, Nudt17, Nudt19, and Dcp2 (Nudt20), and possesses the ability to decap RNA [ 72 , 73 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the demethylase fat mass and obesity-associated protein (FTO) reduce the stability of cGAS mRNA during the progression of cerebral IRI, thereby alleviating brain inflammation by inhibiting the STING/NF-κB axis [ 22 ]. Recently, m7G modification was found to be associated with various diseases, including hepatocellular carcinoma, postischemic angiogenesis, heart failure, and cardiac fibrosis due to myocardial ischemia [ 23 – 25 ]. Similarly, the role of m5C in cells is being gradually recognized, with ALKBH1 being identified as essential for mitochondrial function, thereby influencing atherosclerosis [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

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A comprehensive analysis of m6A/m7G/m5C/m1A-related gene expression and immune infiltration in liver ischemia–reperfusion injury by integrating bioinformatics and machine learning algorithms

Meng,

Li,

et al. 2024

Eur J Med Res

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Background Liver ischemia–reperfusion injury (LIRI) is closely associated with immune infiltration, which commonly occurs after liver surgery, especially liver transplantation. Therefore, it is crucial to identify the genes responsible for LIRI and develop effective therapeutic strategies that target immune response. Methylation modifications in mRNA play various crucial roles in different diseases. This study aimed to identify potential methylation-related markers in patients with LIRI and evaluate the corresponding immune infiltration. Methods Two Gene Expression Omnibus datasets containing human liver transplantation data (GSE12720 and GSE151648) were downloaded for integrated analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted to investigate the functional enrichment of differentially expressed genes (DEGs). Differentially expressed methylation-related genes (DEMRGs) were identified by overlapping DEG sets and 65 genes related to N6-methyladenosine (m6A), 7-methylguanine (m7G), 5-methylcytosine (m5C), and N1-methyladenosine (m1A). To evaluate the relationship between DEMRGs, a protein–protein interaction (PPI) network was utilized. The core DEMRGs were screened using three machine learning algorithms: least absolute shrinkage and selection operator, random forest, and support vector machine-recursive feature elimination. After verifying the diagnostic efficacy using the receiver operating characteristic curve, we validated the expression of the core DEMRGs in clinical samples and performed relative cell biology experiments. Additionally, the immune status of LIRI was comprehensively assessed using the single sample gene set enrichment analysis algorithm. The upstream microRNA and transcription factors of the core DEMRGs were also predicted. Results In total, 2165 upregulated and 3191 downregulated DEGs were identified, mainly enriched in LIRI-related pathways. The intersection of DEGs and methylation-related genes yielded 28 DEMRGs, showing high interaction in the PPI network. Additionally, the core DEMRGs YTHDC1, METTL3, WTAP, and NUDT3 demonstrated satisfactory diagnostic efficacy and significant differential expression and corresponding function based on cell biology experiments. Furthermore, immune infiltration analyses indicated that several immune cells correlated with all core DEMRGs in the LIRI process to varying extents. Conclusions We identified core DEMRGs (YTHDC1, METTL3, WTAP, and NUDT3) associated with immune infiltration in LIRI through bioinformatics and validated them experimentally. This study may provide potential methylation-related gene targets for LIRI immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A comprehensive analysis of m6A/m7G/m5C/m1A-related gene expression and immune infiltration in liver ischemia–reperfusion injury by integrating bioinformatics and machine learning algorithms

Meng,

Li,

et al. 2024

Eur J Med Res

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The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by Regulating SRSF9‐Mediated Splicing of NFATc4

Yu,

Sun,

et al. 2024

Advanced Science

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Cardiac hypertrophy is a key factor driving heart failure (HF), yet its pathogenesis remains incompletely elucidated. Mettl1‐catalyzed RNA N7‐methylguanosine (m7G) modification has been implicated in ischemic cardiac injury and fibrosis. This study aims to elucidate the role of Mettl1 and the mechanism underlying non‐ischemic cardiac hypertrophy and HF. It is found that Mettl1 is upregulated in human failing hearts and hypertrophic murine hearts following transverse aortic constriction (TAC) and Angiotensin II (Ang II) infusion. YY1 acts as a transcriptional factor for Mettl1 during cardiac hypertrophy. Mettl1 knockout alleviates cardiac hypertrophy and dysfunction upon pressure overload from TAC or Ang II stimulation. Conversely, cardiac‐specific overexpression of Mettl1 results in cardiac remodeling. Mechanically, Mettl1 increases SRSF9 expression by inducing m7G modification of SRSF9 mRNA, facilitating alternative splicing and stabilization of NFATc4, thereby promoting cardiac hypertrophy. Moreover, the knockdown of SRSF9 protects against TAC‐ or Mettl1‐induced cardiac hypertrophic phenotypes in vivo and in vitro. The study identifies Mettl1 as a crucial regulator of cardiac hypertrophy, providing a novel therapeutic target for HF.

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The potential of RNA methylation in the treatment of cardiovascular diseases

Wang,

et al. 2024

iScience

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Fibroblast-specific knockout of METTL1 attenuates myocardial infarction-induced cardiac fibrosis

Cited by 8 publications

References 27 publications

A comprehensive analysis of m6A/m7G/m5C/m1A-related gene expression and immune infiltration in liver ischemia–reperfusion injury by integrating bioinformatics and machine learning algorithms

A comprehensive analysis of m6A/m7G/m5C/m1A-related gene expression and immune infiltration in liver ischemia–reperfusion injury by integrating bioinformatics and machine learning algorithms

The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by Regulating SRSF9‐Mediated Splicing of NFATc4

The potential of RNA methylation in the treatment of cardiovascular diseases

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