Increased m6A modification of RNA methylation related to the inhibition of demethylase FTO contributes to MEHP-induced Leydig cell injury☆

Zhao, Tianxin; Wang, Junke; Wu, Yuhao; Han, Lei; Chen, Jiadong; Ya, Wei; Shen, Lianju; Chen, Long; Wu, Shengde; Wei, Guanghui

doi:10.1016/j.envpol.2020.115627

Cited by 49 publications

(23 citation statements)

References 63 publications

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“…In this process, the reads showing adaptor contamination, presenting an N ratio >5%, and containing low-quality sequences were removed. Finally, clean reads were obtained ( Chen et al, 2018 ; Wang et al, 2021 ; Zhao et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Comprehensive Analysis of Transcriptome-wide m6A Methylome Upon Clostridium perfringens Beta2 Toxin Exposure in Porcine Intestinal Epithelial Cells by m6A Sequencing

Zhang

Yang

et al. 2021

Front. Genet.

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Piglet diarrhea is a swine disease responsible for serious economic impacts in the pig industry. Clostridium perfringens beta2 toxin (CPB2), which is a major toxin of C. perfringens type C, may cause intestinal diseases in many domestic animals. N6-methyladenosine (m6A) RNA methylation plays critical roles in many immune and inflammatory diseases in livestock and other animals. However, the role of m6A methylation in porcine intestinal epithelial (IPEC-J2) cells exposed to CPB2 has not been studied. To address this issue, we treated IPEC-J2 cells with CPB2 toxin and then quantified methylation-related enzyme expression by RT-qPCR and assessed the m6A methylation status of the samples by colorimetric N6-methyladenosine quantification. The results showed that the methylation enzymes changed to varying degrees while the m6A methylation level increased (p < 0.01). On this basis, we performed N6-methyladenosine sequencing (m6A-seq) and RNA sequencing (RNA-seq) to examine the detailed m6A modifications and gene expression of the IPEC-J2 cells following CPB2 toxin exposure. Our results indicated that 1,448 m6A modification sites, including 437 up-regulated and 1,011 down-regulated, differed significantly between CPB2 toxin exposed cells and non-exposed cells (p < 0.05). KEGG pathway analysis results showed that m6A peaks up-regulated genes (n = 394) were mainly enriched in cancer, Cushing syndrome and Wnt signaling pathways, while m6A peaks down-regulated genes (n = 920) were mainly associated with apoptosis, small cell lung cancer, and the herpes simplex virus 1 infection signaling pathway. Furthermore, gene expression (RNA-seq data) analysis identified 1,636 differentially expressed genes (DEGs), of which 1,094 were up-regulated and 542 were down-regulated in the toxin exposed group compared with the control group. In addition, the down-regulated genes were involved in the Hippo and Wnt signaling pathways. Interestingly, the combined results of m6A-seq and RNA-seq identified genes with up-regulated m6A peaks but with down-regulated expression, here referred to as “hyper-down” genes (n = 18), which were mainly enriched in the Wnt signaling pathway. Therefore, we speculate that the genes in the Wnt signaling pathway may be modified by m6A methylation in CPB2-induced IPEC-J2 cells. These findings provide new insights enabling further exploration of the mechanisms underlying piglet diarrhea caused by CPB2 toxin.

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Section: Methodsmentioning

confidence: 99%

Comprehensive Analysis of Transcriptome-wide m6A Methylome Upon Clostridium perfringens Beta2 Toxin Exposure in Porcine Intestinal Epithelial Cells by m6A Sequencing

Zhang

Yang

et al. 2021

Front. Genet.

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“…It has also been reported that m 6 A is essential for the well-being of male reproductive system. For instance, the increased m 6 A modification of RNA methylation is related to the inhibition of demethylase FTO thereby contributing to MEHP-induced Leydig cell injury (Zhao et al, 2021). However, it remains unknown whether RNA m 6 A modification is involved in Cr (VI)-induced toxicity in SSCs.…”

Section: Introductionmentioning

confidence: 99%

Melatonin Attenuates Chromium (VI)-Induced Spermatogonial Stem Cell/Progenitor Mitophagy by Restoration of METTL3-Mediated RNA N6-Methyladenosine Modification

Yang

et al. 2021

Front. Cell Dev. Biol.

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Spermatogonial stem cells (SSCs) are the basis of spermatogenesis, and any damage to SSCs may result in spermatogenic disorder and male infertility. Chromium (Cr) (VI) is a proven toxin, mutagen, and carcinogen, perpetually detrimental to environmental organisms due to its intricate and enduring detoxification process in vivo. Despite this, the deleterious effects of Cr (VI) on SSCs and the underlying mechanisms remain poorly understood. In this study, we identified that Cr (VI) impaired male reproductive system in mouse testes and induced mitochondrial dynamic imbalance and mitophagy in SSCs/progenitors. Cr (VI) also downregulated the RNA N6-methyladenosine (m6A) modification levels in mitochondrial dynamic balance and mitophagy genes in SSCs/progenitors. Inspiringly, the toxic effects of Cr (VI) could be relieved by melatonin pretreatment. Melatonin alleviated Cr (VI)-induced damage to male reproductive system and autophagy in mouse testes. Melatonin also attenuated Cr (VI)-induced cell viability loss and reactive oxygen species (ROS) generation, as well as mitochondrial dynamic disorders and mitophagy in SSCs/progenitors. The protective roles of melatonin against Cr (VI)-induced mitophagy were exerted by restoration of METTL3-mediated RNA m6A modification and activation of mitochondrial fusion proteins MFN2 and OPA1, as well as inhibition of the mitophagy BNIP3/NIX receptor pathway. Thus, our study provides novel insights into the molecular mechanisms for RNA m6A modification underlying the gene regulatory network responsible for mitochondrial dynamic balance, and also lays new experimental groundwork for treatment of Cr (VI)-induced damage to male fertility.

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“…In addition, the regulatory factor of m6A RNA methylation has been shown to promote the malignant progression of LUAD and has clinical diagnostic, progressive and prognostic properties (7,8). FTO induces NELL2 expression, which leads to the metastasis of non-small cell lung cancer via the inhibition of E2F1 m6A modification (27,28) and regulates melanoma tumorigenicity and response to anti-PD-1 blockade (29). Thus, in our study, FTO was identified as a potential prognostic biomarker of LUSC.…”

Section: Discussionmentioning

confidence: 99%

An integrated model of FTO and METTL3 expression that predicts prognosis in lung squamous cell carcinoma patients

Zhang¹,

Han²,

Zhao³

et al. 2021

Ann Transl Med

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Background: Lung squamous cell carcinoma (LUSC) approximately accounts for a third of lung cancers.However, the role of N6-methyladenosine (m6A) in LUSC remains largely unknown according to previous studies. Methods:In this study, we investigated the mutations, copy number variants (CNVs), expression of 20 m6A RNA methylation regulators, and clinical data from The Cancer Genome Atlas-LUSC (TCGA-LUSC). These data were used for the training cohort of screening potential biomarkers. The prognostic model of m6A RNA methylation regulators was constructed. A receiver operating characteristic (ROC) analysis was undertaken to determine the area under the curves (AUCs) (for 3-and 5-year survival) for the model. Additionally, the accuracy of the two-gene model was confirmed with external data verifications.Combined two-gene model and clinincal information were performed to construct a nomogram to predict patient's prognostic risk assessment.Results: Fat mass-and obesity-associated protein (FTO) and methyltransferase-like 3 (METTL3) were identified as potential prognostic biomarkers to evaluate benign and malignant tumors and prognosticate.The following prognostic model of m6A RNA methylation regulators was constructed: risk score = 0.162 × FTO − 0.069 × METTL3. Patients in low-risk group [median overall survival (mOS), 43.4 months] had longer survival than those with high-risk (mOS, 67.3 months) with P=0.0023. The smoking grade and risk score could be independent prognostic factors (P=0.00098 and P=0.0014, respectively). Ultimately, a nomogram was developed to assist clinicians to predict clinical outcomes.Conclusions: FTO and METTL3 are potential prognostic biomarkers of LUSC. The two-gene model's use of prognostic risk scores may provide guidance in the selection of therapeutic strategies.

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Increased m6A modification of RNA methylation related to the inhibition of demethylase FTO contributes to MEHP-induced Leydig cell injury☆

Cited by 49 publications

References 63 publications

Comprehensive Analysis of Transcriptome-wide m6A Methylome Upon Clostridium perfringens Beta2 Toxin Exposure in Porcine Intestinal Epithelial Cells by m6A Sequencing

Comprehensive Analysis of Transcriptome-wide m6A Methylome Upon Clostridium perfringens Beta2 Toxin Exposure in Porcine Intestinal Epithelial Cells by m6A Sequencing

Melatonin Attenuates Chromium (VI)-Induced Spermatogonial Stem Cell/Progenitor Mitophagy by Restoration of METTL3-Mediated RNA N6-Methyladenosine Modification

An integrated model of FTO and METTL3 expression that predicts prognosis in lung squamous cell carcinoma patients

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