CELLULAR SIGNALLING
·
2025
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IF 3.7
Tingjuan Huang,Ziyi Shang,Lina Nie,Haichao Diao,Qizhi Shuai,Junjie Ren,Jun Xu,Jun Xie
Hepatic stellate cells (HSCs) are the central link of the occurrence and development of hepatic fibrosis, and autophagy promotes HSCs activation. N6-methyladenosine (m6A) RNA modification can also control autophagy by targeting selected autophagy-associated genes. but up to now, little research has been done on the m6A modification autophagy-related genes (ATGs) in hepatic fibrosis. Here, we identify ATG9A as a previously unrecognized m6A modified ATG using m6A-sequencing (m6A-seq). Importantly, ATG9A is upregulated in liver fibrosis mice and primary biliary cirrhosis (PBC) patient liver tissue. Mechanistically, based on the presence of m6A binding sites on ATG9A, ATG9A promotes HSCs autophagy in an m6A dependent manner, thereby enhancing HSCs activation. Noteworthy, FTO is identified as the upstream of ATG9A, and knockdown of ATG9A can prevent FTO-induced HSCs autophagy and activation. In bile duct ligation (BDL) or CCL4-induced liver fibrosis mouse models, lowering ATG9A alleviated liver fibrosis through PI3K/AKT/mTOR pathway and TGFβ1/smad3 pathway. Taken together, our results provided that ATG9A is a potential prognostic biomarker and therapeutic target for patients with liver fibrosis.
研究领域:
分子生物学
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遗传学
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肝病学
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DOI
PubMed
高影响因子
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
✓ 已验证
DOI
PubMed
高影响因子
iScience
·
2024
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IF 4.6
Lele Xu,Yuting Chen,Tao Wu,Jiaqi Fan,Yuying Hu,Xuefeng Gao,Yuliang Wang,Tao Chen,Xueting Zhao,Min Zeng,Fei Wang,Qingyou Zheng,Xiaojuan Pei,Dinglan Wu
Polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) represent a promising novel treatment for castration-resistant prostate cancer (CRPC) with encouraging results. However, the combination targets in CRPC remain largely unexplored. N6-methyladenosine (m 6 A) has been shown to play a crucial role in cancer progression and DNA damage response. Here, we observed a higher overall level of m 6 A and a downregulation of Fat mass and obesity-associated protein (FTO), which correlated with unfavorable clinicopathological parameters in prostate cancer (PCa). Functionally, reduced FTO promotes PCa growth, while overexpression of FTO has the opposite effect. Mechanistically, FOXO3a was identified as the downstream target of FTO in PCa. FTO downregulates the expression of FOXO3a in an m 6 A-dependent manner, leading to the degradation of its mRNA. Importantly, DNA damage can degrade FTO through the ubiquitination pathway. Finally, we found that overexpression of FTO can enhance the effect of PARPi on PCa. Therefore, our findings may provide insight into novel therapeutic approaches for CRPC.
研究领域:
癌症生物学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
CANCER LETTERS
·
2023
·
IF 9.7
Jiaoshun Chen,Haoxiang Zhang,Chaoyang Xiu,Chenggang Gao,Shihong Wu,Jianwei Bai,Qiang Shen,Tao Yin
In eukaryotes, N 6 -methyladenosine (m6A) is the most prevalent epigenetic alteration. Methyltransferase-like 3 (METTL3) is a key player in the control of m6A, although its function in pancreatic cancer is incompletely understood. In this study, we examined the role that METTL3 plays in pancreatic cancer cell proliferation and stemness. We discovered that in pancreatic cancer cells, METTL3-mediated m6A alterations regulate ID2 as a downstream target. The stability of ID2 mRNA was decreased and m6A modification was effectively eliminated by METTL3 knockdown in pancreatic cancer cells. We also demonstrate that m6a-YTHDF2 is necessary for the METTL3-mediated stabilization of ID2 mRNA. Additionally, we show that ID2 controls the stemness molecules NANOG and SOX2 via the PI3K-AKT pathway to support pancreatic cancer growth and stemness maintenance. Our data suggest that METTL3 may post-transcriptionally upregulate ID2 expression in an m6A-YTHDF2-dependent manner to further promote the stabilization of ID2 mRNA, which may be a new target for pancreatic cancer treatment.
研究领域:
癌症生物学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2021
·
IF 6.291
Luyao Li,Mei Zhou,Biyun Chen,Qin Wang,Shuya Pan,Yaxuan Hou,Jiamin Xia,Xue Zhou
Cadmium is a carcinogenic heavy metal that poses a severe threat to human beings. The underlying mechanism, however, remains elusive. N6-methyladenosine (m6A) is the most abundant post-transcriptional modification in mRNA that regulates RNA metabolism. Emerging evidence shows that m6A is involved in the pathogenesis of various cancers. In this study, human bronchial epithelial BEAS-2B cells were transformed by exposing to 2 μM of cadmium for 20 weeks to investigate the role of m6A in cadmium carcinogenesis. We found the level of m6A in mRNA was significantly decreased in cadmium-transformed BEAS-2B cells, and this change was regulated by m6A demethylase ALKBH5. ALKBH5 was significantly upregulated in the middle and late stages of cell transformation at week 8, 12, 16 and 20. Knockdown of ALKBH5 in cadmium-transformed cells alleviated cell proliferation, migration, invasion, and anchorage-independent growth, but co-transfection with ALKBH5 siRNA and PTEN siRNA restored the inhibitory effects of ALKBH5 knockdown on those transformation properties. ALKBH5 decreased the m6A level of PTEN mRNA, resulting in its instability and reduction of PTEN protein expression. These results indicate that ALKBH5-mediated demethylation m6A at PTEN mRNA is involved in cadmium-induced cell transformation. Our study provides a new perspective for the involvement of m6A modification in cadmium carcinogenesis.
研究领域:
毒理学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2025
·
IF 6.9
Zhuo Li,Zhengnan Guo,Zhengmeng Yang,Boguang Yang,Yuan Hu,Xian Xie,Zhixian Zong,Zekun Chen,Kunyu Zhang,Pengchao Zhao,Gang Li,Xuefeng Yang,Liming Bian
Intramembranous ossification, a major bone development process, begins with the condensation of precursor cells through the timely structural adaption of extracellular matrix (ECM) catering to rapid cellular morphological changes. Inspired by this, we design a highly cell-adaptable hydrogel to recapitulate an ECM-dependent mechanotransduction-metabolism-epitranscriptomics axis in mesenchymal stromal cells (MSCs). This hydrogel significantly enhances the E-cadherin-mediated cell-cell interactions of MSCs and promotes glucose uptake and tricarboxylic acid (TCA) cycle activities. We further show that elevated succinate inhibits fat mass and obesity-associated protein (FTO), a N6-methyladenosine (m 6 A) demethylase, thereby enhancing methyltransferase-like 3 (METTL3)-driven m 6 A methylation. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) indicates increased m 6 A methylation of runt-related transcription 2 (Runx2), a key osteogenic signaling factor, promoting osteogenesis of hydrogel-delivered MSCs and bone regeneration in critical-sized bone defects. Our findings reveal the mechanism underlying the critical impact of adaptable ECM structures on tissue development and provide valuable guidance for the design of ECM-mimetic cell carriers to enhance the therapeutic outcomes of regenerative medicine.
研究领域:
细胞生物学
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分子生物学
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再生医学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Xiao-Yi Zhang,Yi-Hao Zhang,Nan-Nan Liang,Shan-Shan Xu,Qiang-Sheng Li,Ya-Ping Song,Wei-Wei Zhang,Bo Wang,Hua Wang,Yi-Chao Huang,De-Xiang Xu
Accumulating evidence indicates that arsenic (As) exposure causes a decline in sperm quality. This study aimed to investigate the impact of As exposure on spermatogonial senescence. GC-1 cells were exposed to NaAsO 2 (10 μM). RNA sequencing and ribosome profiling sequencing were performed to identify key regulators of cellular senescence. Methylated RNA immunoprecipitation-qPCR was used to determine N 6 -methyladenosine (m6A) modification. The results revealed that the differentially expressed genes were enriched in pathways related to cellular senescence. Several established senescence markers, β-galactosidase activity, γ-H2AX, and P16, were elevated in As-exposed GC-1 cells. Further analysis revealed that P21 and its transcription factor ETS2 were upregulated. ETS2 knockout prevented As-induced P21 upregulation and cell senescence. The multi-omics joint analysis indicated that As exposure elevated ETS2 translation efficiency by YTHDC2-dependent m6A modification. Mechanistically, As exposure induced mitochondrial dysfunction. Alpha-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate and RNA demethylase cofactor, was reduced in As-exposed GC-1 cells. Additional experiments showed that As exposure induced NAD + depletion and suppressed SIRT3 activity. Supplementation with nicotinamide mononucleotide, an NAD + precursor, attenuated As-evoked α-KG reduction and ETS2 upregulation. These findings suggest that As induces spermatogonial senescence via m6A modification-mediated upregulation of ETS2 translation and identify NAD + replenishment as a potential countermeasure.
研究领域:
毒理学
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分子生物学
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表观遗传学
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生殖生物学
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生物信息学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Genetics
·
2021
·
IF 4.599
Yang Hong,Wu Yi-Fan,Ding Jie,Liu Wei,Zhu De-Sheng,Shen Xia-Feng,Guan Yang-Tai
Background: N6-Methyladenosine (m6A) methylation is the most prevalent internal posttranscriptional modification on mammalian mRNA. But its role in neuromyelitis optica spectrum disorders (NMOSD) is not known.Aims: To explore the mechanism of m6A in NMOSD patients.Methods: This study assessed the m6A methylation levels in blood from two groups: NMOSD patients and healthy controls. Methylated RNA immunoprecipitation Sequencing (MeRIP-seq) and RNA-seq were performed to assess differences in m6A methylation between NMOSD patients and healthy controls. Ultra-high performance liquid chromatography coupled with triple quadruple mass spectrometry (UPLC-QQQ-MS) method was performed to check m6A level. Differential m6A methylation genes were validated by MeRIP-qPCR.Results: Compared with that in the control group, the total m6A level was decreased in the NMOSD group. Genes with upregulated methylation were primarily enriched in processes associated with RNA splicing, mRNA processing, and innate immune response, while genes with downregulated methylation were enriched in processes associated with the regulation of transcription, DNA-templating, and the positive regulation of I-kappa B kinase/NF-kappa B signalling.Conclusion: These findings demonstrate that differential m6A methylation may act on functional genes to regulate immune homeostasis in NMOSD.
研究领域:
神经病学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2025
·
IF 6.9
Ri-Xin Chen,Ao-Tian Mo,Shui-Dan Xu,Jun-Han Wu,Min-Hua Deng,Shu-Huan Xie,Wei-Tao Zhuang,Jin-Ling Duan,Han Yang,Peng Lin,Zhe He,Ji-Ming Tang,Hai-Yu Zhou,Xiao-Song Ben,Gui-Bin Qiao,Dan Xie
RNAs and RNA-binding proteins (RBPs) play crucial roles in stress granule (SG) dynamics, yet the specific interactions between SG-associated circular RNAs (circRNAs) and RBPs in esophageal squamous cell carcinoma (ESCC) remain unclear. In this study, we identified m6A-modified circG3BP1 as a potential prognostic biomarker in ESCC. Under cisplatin-induced stress, IGF2BPs facilitate the m6A-dependent translocation of circG3BP1 to SGs, where it functions as a scaffold to enhance TIAR-CAPRIN1 interactions, thereby promoting SG nucleation. SG formation suppresses the translation of senescence-associated mRNAs, such as p21 , delaying chemotherapy-induced cellular senescence and contributing to cisplatin resistance in ESCC cells. Clinically, elevated circG3BP1 expression is associated with cisplatin resistance in patients with ESCC. These findings reveal a previously uncharacterized m6A-dependent mechanism by which circG3BP1 promotes SG-mediated chemoresistance, providing a promising potential biomarker and therapeutic target for ESCC treatment.
研究领域:
肿瘤学
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分子生物学
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RNA生物学
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转化医学
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表观遗传学
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细胞应激反应
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
AGING CELL
·
2025
·
IF 7.1
Yu Zhang,Xiaojie Liu,Hairong Lian,Yanchao Chai,Yang Zhou,Dongqi Kan,Jilong Ren,Cui Han,Jiaxin Yang
Metformin, a medication primarily used to treat diabetes, has gained attentions for its potential antiaging properties. Although the metabolic and cellular pathways behind its longevity effects have been widely studied, few studies have explored the epigenetic regulatory effects of metformin, which are a crucial factor in aging processes. In this study, we examined the antiaging effects of metformin using the Brachionus rotifer as a model, focusing on the regulation of mRNA N6–methyladenosine (m6A), a key RNA modification involved in mRNA stability, translation, and splicing. We found metformin significantly extended the rotifers' lifespan, mimicking the effects of dietary restriction (DR), a well–established antiaging intervention. Both metformin and DR modulate m6A dynamics, with a notable reduction in the m6A modification of MTR (5–methyltetrahydrofolate–homocysteine methyltransferase). This reduction led to decreased MTR expression and lowered levels of S–adenosylmethionine (SAM), a critical metabolite in the one–carbon cycle. We propose that the downregulation of MTR through m6A modification limits methionine synthesis and imposes methionine restriction, a key factor in promoting longevity. Our findings reveal a novel epitranscriptional regulatory model by which metformin and DR modulate m6A to extend lifespan, highlighting MTR as a central regulator of aging and suggesting potential therapeutic strategies for healthy aging through m6A and methionine metabolism.
研究领域:
遗传学
·
表观遗传学
·
分子生物学
·
衰老研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Jianan Yang,Tonglian Jiang,Xun Lu,Xiang li,Xuling Zhou,Xinxin Guo,Chengxin Ma,Xiaobei Xie,Dongxiao Li,Siqi Yu,Jiayi An,Binghai Zhao,Hongzhi Li
Hyperuricemia is a known risk factor for chronic kidney disease (CKD) and subsequent renal fibrosis. N6-methyladenosine (m6A) is the most prevalent chemical modification in eukaryotic mRNAs and has been implicated in various diseases. However, its role in hyperuricemic nephropathy (HN) remains unclear. This study investigated the involvement of the methylase METTL14 in HN pathogenesis. Our in vitro and in vivo function experiments demonstrated that METTL14 plays a crucial role in HN. In mouse models of uric acid (UA)-induced renal injury, we detected impaired kidney function, increased renal interstitial fibrosis, and significantly decreased m6A methylation levels in renal tissues. Treatment with benzbromarone, a UA-lowering drug, alleviated renal injury, restored m6A methylation levels, and upregulated METTL14 expression. Cellular experiments showed that METTL14 overexpression attenuated high UA-induced fibrosis in renal tubular epithelial cells. This overexpression significantly decreases the expression of GLUT9, a key protein involved in UA transport, leading to reduced UA reabsorption. Additionally, MeRIP-qPCR and dual-luciferase reporter gene experiments further demonstrated that METTL14 overexpression enhanced Glut9 mRNA m6A methylation modification, accelerating its degradation and decreasing expression levels. Thus, METTL14-mediated RNA m6A modification plays a role in the renal tubular epithelial cell damage induced by high UA, by regulating Glut9 mRNA post-transcriptionally. These findings provide valuable insights for the diagnosis and development of therapeutic drugs for HN.
研究领域:
肾病学
·
分子生物学
·
表观遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2021
·
IF 7.963
Limei Sun,Ming Gao,Qiuhui Qian,Ziyi Guo,Peng Zhu,Xuedong Wang,Huili Wang
Chronic exposure of triclosan (TCS) to zebrafish triggers high incidence of fatty liver and hepatitis; however, the underlying molecular mechanisms remain unclear. Herein, we identified miR-30b as a sensitive biomarker to TCS stress, reflecting in that its decreased expression caused metabolic toxicity, abnormal development and behavior, and lipid-metabolism disorder. By microinjecting the inhibitor and mimic experiments, miR-30b was proved to regulate lipid metabolism by its main target gene fto . Over-expression of FTO resulted in fat accumulation, elevation of the TG and TC levels and up-regulation of the PPARγ and CEBPα, as well as decrease of the global m 6 A level in larvae. On the contrary, the knock-down of FTO using MO caused the anti-lipogenic effect, decrease of the TG and T-CHO levels, and abnormal changes of cebpɑ , acsl 5, fasn , ppap 2c and ppar γ etc. Further fortification tests of cycloleucine and betaine evidenced that the toxic effect was strongly dependent on regulation of the m 6 A level. The toxicity effects in the treatments of methylated donors and receptors were consistent with the changes in physiological functions of FTO knockdown and overexpression. The effects of cycloleucine on m 6 A level and lipid metabolism generally consisted with those of FTO, but this was not the case for betaine, reflecting in increased m 6 A level and lipid accumulation in larval liver. Consequently, we posit that TCS exposure caused zebrafish lipid-metabolism disorder by decreasing miR-30b expression to regulate fto-mediated m 6 A methylation level. These findings contribute to our deep understanding of the underlying molecular mechanisms regarding contaminant-originating fatty liver and hepatocellular carcinoma, and also have practical significance in pollution warning and target therapy for related diseases.
研究领域:
毒理学
·
分子生物学
·
环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）