Nature Communications
·
2022
·Vol. 13
·期 1
·1-23
·
IF 17.694
Hao WeiChao,Dian MeiJuan,Zhou Ying,Zhong QiuLing,Pang WenQian,Li ZiJian,Zhao YaYan,Ma JiaCheng,Lin XiaoLin,Luo RenRu,Li YongLong,Jia JunShuang,Shen HongFen,Huang ShiHao,Dai GuanQi,Wang JiaHong,Sun Yan,Xiao Dong
Autophagy is crucial for maintaining cellular energy homeostasis and for cells to adapt to nutrient deficiency, and nutrient sensors regulating autophagy have been reported previously. However, the role of eiptranscriptomic modifications such as m 6 A in the regulation of starvation-induced autophagy is unclear. Here, we show that the m 6 A reader YTHDF3 is essential for autophagy induction. m 6 A modification is up-regulated to promote autophagosome formation and lysosomal degradation upon nutrient deficiency. METTL3 depletion leads to a loss of functional m 6 A modification and inhibits YTHDF3-mediated autophagy flux. YTHDF3 promotes autophagy by recognizing m 6 A modification sites around the stop codon of FOXO3 mRNA. YTHDF3 also recruits eIF3a and eIF4B to facilitate FOXO3 translation, subsequently initiating autophagy. Overall, our study demonstrates that the epitranscriptome regulator YTHDF3 functions as a nutrient responder, providing a glimpse into the post-transcriptional RNA modifications that regulate metabolic homeostasis.
研究领域:
细胞生物学
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分子生物学
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表观遗传学
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DOI
PubMed
高影响因子
PLoS One
·
2024
·Vol. 19
·期 8
·e0306043
·
IF 2.9
Yuping Liao,Feng Zhang,Fang Yang,Shijin Huang,Sha Su,Xuemei Tan,Linlin Zhong,Lingjie Deng,Lihong Pang
Background
Haemoglobin H (HbH) disease is caused by a disorder of α-globin synthesis, and it results in a wide range of clinical symptoms. M 6 A methylation modification may be one of the mechanisms of heterogeneity. Therefore, this article explored the role of methyltransferase like 16 (METTL16) in HbH disease.
Method
The results of epigenetic transcriptome microarray were analysed and verified through bioinformatic methods and qRT-PCR, respectively. The overexpression or knock down of METTL16 in K562 cells was examined to determine its role in reactive oxygen species (ROS), cell cycle processes or iron overload. YTH domain family protein 3 (YTHDF3) was knocked down in K562 cells and K562 cells overexpressing METTL16 via siRNA to investigate its function. In addition, haemoglobin expression was detected through benzidine staining. qRT-PCR, WB, methylated RNA Immunoprecipitation (MeRIP) and (RNA Immunoprecipitation) RIP experiments were conducted to explore the mechanism of intermolecular interaction.
Results
METTL16, YTHDF3 and solute carrier family 5 member 3 (SLC5A3) mRNA and the methylation level of SLC5A3 mRNA were downregulated in HbH patients. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) mRNA expression was negatively correlated with HGB content among patients with HbH-CS disease. Overexpression of METTL16 increased ROS and intracellular iron contents in K562 cells, changed the K562 cell cycle, reduced hemin-induced haemoglobin synthesis, increased the expressions of SLC5A3 and HBG and increased SLC5A3 mRNA methylation levels. Knockdown of METTL16 reduced ROS and intracellular iron contents in K562 cells. Hemin treatment of K562 cells for more than 14 days reduced the protein expressions of METTL16 and SLC5A3 and SLC5A3 mRNA methylation levels. Knockdown of YTHDF3 rescued the intracellular iron content changes induced by the overexpression of METTL16. The RIP experiment revealed that SLC5A3 mRNA can be enriched by METTL16 antibody.
Conclusion
METTL16 may affect the expression of SLC5A3 by changing its m 6 A modification level and regulating ROS synthesis, intracellular iron and cycle of red blood cells. Moreover, METTL16 possibly affects the expression of haemoglobin through IGF2BP3, which regulates the clinical phenotype of HbH disease.
研究领域:
分子生物学
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血液学
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表观遗传学
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细胞生物学
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DOI
PubMed
高影响因子
Molecular Metabolism
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2026
·
IF 6.3
Weiyan Wang,Lingli Xie,Guilan Chen,Xin Zuo,Meiling Zhong,Tong Yang,Weihua Wu
Background Diabetic cardiomyopathy (DCM) is a prevalent and severe cardiovascular complication of diabetes mellitus, characterized by progressive cardiac dysfunction and pathological remodeling driven by myocardial metabolic disturbances. However, the underlying molecular mechanisms remain incompletely elucidated. Methods A type 2 DCM mouse model was established by feeding C57BL/6 mice a high-fat diet combined with streptozotocin injections. Cardiomyocyte-specific TRIM47 knockdown was achieved via AAV9-mediated delivery of a cardiomyocyte-specific cTnT promoter-driven shRNA. In vitro, primary neonatal mouse ventricular cardiomyocytes (NMCMs) were treated with palmitic acid (PA) to model cardiomyocyte injury. Results TRIM47 was significantly upregulated in diabetic hearts. Cardiomyocyte-specific TRIM47 knockdown improved left ventricular ejection fraction and fractional shortening, attenuated chamber dilation, and reduced heart weight-to-tibia length ratio. TRIM47 silencing attenuated cardiomyocyte hypertrophy, interstitial fibrosis, and cardiomyocyte apoptosis, alongside reduced myocardial inflammatory cytokine levels (TNF-α, IL-6, IL-1β). Furthermore, TRIM47 knockdown alleviated myocardial lipid accumulation and reduced triglyceride levels, accompanied by downregulation of the fatty acid translocase CD36. In vitro, PA-treated NMCMs exhibited elevated TRIM47 expression, and its knockdown mitigated PA-induced cardiomyocyte injury, inflammation, apoptosis, and lipid deposition. Mechanistically, the m6A reader YTHDF3 was upregulated under PA conditions and directly bound to m6A-modified TRIM47 mRNA, enhancing its stability. Rescue experiments demonstrated that YTHDF3 overexpression exacerbated PA-induced cardiomyocyte injury, whereas concurrent TRIM47 knockdown largely reversed these deleterious effects. Conclusions Our results revealed that TRIM47 may contribute to the progression of DCM by promoting abnormal cardiac lipid metabolism, exacerbating inflammation and apoptosis, and these effects are partially mediated through the upstream m6A reader YTHDF3.
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DOI
PubMed
高影响因子
LIFE SCIENCES
·
2026
·
IF 6.4
Fengzhen Huang,Jiping Yi,Tieqiao Zhou,Jibao Wu,Xiaojing Li,Heng Meng,Xiaoxiang Gong
Background YTHDF3 expression is up-regulated in sepsis-associated encephalopathy (SAE), yet its precise function remains to be fully elucidated. This study aims to investigate the role of YTHDF3 in microglial pyroptosis during SAE and to explore its upstream and downstream regulatory mechanisms. Methods Lipopolysaccharide (LPS) induced SAE models were established in mice and primary microglia for the assessment of YTHDF3 and pyroptosis levels. Downstream targets of YTHDF3 were identified through RNA sequencing and RNA immunoprecipitation. Ultimately, chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) was utilized to confirm H3K18la enrichment at the YTHDF3 promoter. Results In both in vitro and in vivo models of SAE, YTHDF3 expression was significantly upregulated. Crucially, YTHDF3 knockdown effectively attenuated NLRP3-mediated microglial pyroptosis, thereby alleviating neuroinflammation and restoring cognitive function in SAE mice. Mechanistically, Usp9x acted as a direct downstream target of YTHDF3 to mediate the deubiquitination of NLRP3, which in turn augmented microglial pyroptosis in SAE. Furthermore, the transcriptional upregulation of YTHDF3 was promoted by H3K18la enrichment at its promoter. Inhibition of the lactylation-driven YTHDF3/Usp9x/NLRP3 signaling axis attenuates microglial pyroptosis and ameliorates cognitive dysfunction in SAE models. Conclusion Lactylation-driven YTHDF3 promotes microglial pyroptosis and cognitive impairment in SAE by targeting the Usp9x/NLRP3 axis. Our findings highlight this axis as a potential therapeutic target for SAE. Download: Download high-res image (123KB) Download: Download full-size image
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产品关联
DOI
高影响因子
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
·
2026
·
IF 3.5
Xiaoran Sun,Yifan Chen,Kunyi Liu,Yi Si,Mingda Xuan,Rui Zhang,Jiao Jiao,Ting Liu,Shuangshuang Han,Jia Wang,Weifang Yu
Objective Gastric cancer remains a major global health burden. This study aimed to investigate the biological function, clinical significance, and underlying molecular mechanism of the RNA-binding protein YTHDF3 in gastric cancer (GC) progression. Methods YTHDF3 expression was analyzed using public databases (TCGA, GEO), clinical GC specimens (IHC, RT-qPCR), and GC cell lines. Functional roles were assessed through in vitro proliferation, migration, invasion, and apoptosis assays following YTHDF3 knockdown or overexpression, and via an in vivo subcutaneous tumor model. Mechanistic insights were gained through RNA sequencing, RIP-qPCR, dual-luciferase reporter assay, co-immunofluorescence, rescue experiments, and western blotting to identify downstream targets and signaling pathways. Results YTHDF3 was significantly upregulated in GC tissues, correlating with lymph node metastasis and advanced TNM stage. In vitro, YTHDF3 knockdown inhibited GC cell proliferation, migration, and invasion while promoting apoptosis, whereas its overexpression had the opposite effects. In vivo, YTHDF3 knockdown suppressed tumor growth. Mechanistically, YTHDF3 directly bound to and stabilized NEK7 mRNA. NEK7 was highly expressed in GC and crucial for YTHDF3-mediated oncogenic effects. Furthermore, YTHDF3 promoted GC progression by activating the Wnt/β-catenin signaling pathway via NEK7, which was validated using a pathway inhibitor (IWR-1-endo). Conclusion This study identifies the YTHDF3/NEK7 axis as a key regulator of GC progression via activation of the Wnt/β-catenin pathway. YTHDF3 represents a potential prognostic biomarker and a promising therapeutic target for GC. Graphical YTHDF3 binds to and stabilizes NEK7 mRNA in an m6A-dependent manner, thereby activating the Wnt/β-catenin signaling pathway and promoting gastric cancer progression. This study identifies the YTHDF3/NEK7 axis as a potential prognostic biomarker and therapeutic target in gastric cancer.
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Jingyu Wang,Xiaoli Guo,Yujiao Chen,Wei Zhang,Jing Ren,Ai Gao
Chronic benzene exposure causes hematotoxicity, yet the underlying molecular mechanisms remain incompletely understood. N6-methyladenosine (m6A) RNA modification has emerged as a critical regulator in various diseases, but its role in benzene-induced hematotoxicity is unclear. In this study, m6A mRNA microarray analysis revealed widespread alterations in m6A methylation following benzene exposure. Gene Ontology (GO) enrichment identified ubiquitin conjugating enzyme E2 G2 (UBE2G2) as a key m6A-methylated transcript associated with protein degradation pathways. Bioinformatics prediction and experimental validation (RIP-qPCR and MeRIP-qPCR) confirmed that the m6A reader YTHDF3 directly binds to UBE2G2 mRNA in an m6A-dependent manner. Benzene exposure downregulated YTHDF3 expression, leading to decreased UBE2G2 mRNA stability and expression. Overexpression of YTHDF3 reversed this suppression, confirming the regulatory relationship. Functionally, reduced UBE2G2 impaired ubiquitination of acyl-CoA synthetase long-chain family member 4 (ACSL4), resulting in its stabilization and upregulation, which promoted lipid peroxidation and ferroptosis. Notably, melatonin treatment ameliorated benzene-induced hematotoxicity by restoring the YTHDF3/UBE2G2/ACSL4 axis. In summary, this study identifies a novel epigenetic pathway—YTHDF3/m6A/UBE2G2/ACSL4—that mediates benzene-induced ferroptosis, and demonstrates the protective effect of melatonin through modulation of this axis.
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DOI
PubMed
高影响因子
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