Cell Metabolism
·
2025
·
IF 30.9
Zhou-Li Cheng,Shuyuan Zhang,Zhenning Wang,Aixia Song,Chao Gao,Jun-Bin Song,Pu Wang,Lei Zhang,Yue Zhou,Wenyan Shan,Chen Zhang,Jinye Zhang,Yiping Sun,Yanhui Xu,Fei Lan,Ming Zhong,Liang-Dong Lyu,Guanghua Huang,Fei Xavier Chen,Gang Li,Zixin Wang,Faying Chen,Jianhuang Xue,Jiejun Shi,Yujun Liu,Zihao Lin,Duojiao Wu,Jim Na,Lei-Lei Chen,Kun-Liang Guan,Yue Xiong,Dan Ye
Pathogenic bacterial persistence enables survival during antibiotic treatment, leading to treatment failure and recurrent infections, yet its underlying mechanisms remain unclear. Here, we reveal that glyoxylate, a metabolite originally evolved for alternative carbon utilization, functions as a signaling molecule to reprogram the host transcriptome and promote persister formation. Glyoxylate inhibits the DNA dioxygenase TET2, suppressing pro-inflammatory gene expression and attenuating host immune defense. Notably, stimulating TET2 activity with vitamin C or blocking glyoxylate production by Salmonella reduces bacterial antibiotic resistance and improves infection treatment outcomes. Beyond its metabolic role, glyoxylate emerges as a regulator of host-pathogen interactions, while TET2 plays a critical role in preventing bacterial persistence. Our findings suggest that targeting glyoxylate production or enhancing TET2 activity offers promising therapeutic strategies to combat bacterial persistence and enhance the efficacy of antibiotic treatments.
研究领域:
微生物学
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免疫学
·
表观遗传学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL MEDICINE
·
2024
·Vol. 221
·期 7
·e20240111
·
IF 12.6
Xue Yun,Chen Yuting,Sun Sijia,Tong Xinyuan,Chen Yujia,Tang Shijie,Wang Xue,Bi Simin,Qiu Yuqin,Zhao Qiqi,Qin Zhen,Xu Qin,Ai Yingjie,Chen Leilei,Zhang Beizhen,Liu Zhijie,Ji Minbiao,Lang Meidong,Chen Luonan,Xu Guoliang,Hu Liang,Ye Dan,Ji Hongbin
Phenotypic plasticity is a rising cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung cancer. Here, we find that ten-eleven translocation (TET)–mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that Tet2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3–CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to–cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.
研究领域:
肿瘤学
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免疫学
·
分子生物学
·
癌症生物学
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DOI
PubMed
高影响因子
Clinical and Experimental Otorhinolaryngology
·
2023
·
IF 3
Kunyu Liu,Yu Xu
Objectives. Hypoxia-inducible factor 1α (HIF1α) and Tet methylcytosine dioxygenase 2 (TET2) have been reported to mediate nasal polypogenesis through the epithelial-to-mesenchymal transition (EMT). Additionally, HIF1α can regulate the expression and function of TET2. However, the precise mechanism of how TET2 regulates the EMT through HIF1α mediation in nasal epithelial cells is still poorly understood. Methods. Nasal tissue samples were collected from patients with chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps (CRSsNP), and controls. The expression of HIF1α and TET2 was detected using Western blotting and immunohistochemistry. EMT markers (E-cadherin and vimentin) were also evaluated by immunohistochemistry. Primary human nasal epithelial cells (hNECs) were stimulated with CoCl 2 to mimic hypoxia. Vitamin C (VC), a TET2 non-specific activator, and small interfering RNA (siRNA) transfection of TET2 were used to further determine the role of TET2 in hypoxia-induced EMT. Finally, reactive oxygen species (ROS) and Nrf2 were measured to explore the downstream consequences of TET2 in hypoxic hNECs. Results. TET2 levels were lower in the nasal epithelium of CRSwNP patients and were positively correlated with E-cadherin but negatively correlated with vimentin in CRS. However, HIF1α exhibited the opposite pattern and was negatively correlated with TET2 expression. CoCl 2 -simulated hypoxia led to EMT and increased HIF1α in hNECs in vitro , with simultaneous downregulation of TET2 expression. Addition of VC activated TET2 expression in hNECs, but inhibited EMT and HIF1α expression. Furthermore, siRNA knockdown of TET2 contributed to the EMT in CoCl 2 -simulated hNECs despite the addition of VC. Finally, TET2 regulated the EMT in hypoxic hNECs through Nrf2 expression and ROS generation. Conclusion. TET2 was negatively correlated with HIF1α and EMT in vivo . TET2 was downregulated by HIF1α, resulting in the EMT in CoCl 2 -hypoxic hNECs via regulation of oxidative stress in vitro . Hence, TET2 might provide a new therapeutic approach for CRSwNP
研究领域:
免疫学
·
耳鼻喉科学
·
分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2017
·
IF 3.937
Shanqi Guo,Xingkang Jiang,Yuanyuan Wang,Liwei Chen,Huzi Li,Xiaojiang Li,Yingjie Jia
Although previous studies suggested that stress erythropoiesis and iron metabolism regulate each other to increase iron availability for hemoglobin synthesis , the molecular bases determining its different traits remain elusive. In addition, global DNA demethylation has been reported during mouse erythropoiesis in vivo . However, the understanding of iron-related genes through DNA demethylation under stress erythropoiesis is largely unknown. In the current study, we found disordered iron homeostasis and misregulated hepcidin-ferroportin axis under stress erythropoiesis. Interestingly, global 5hmC content and TET2 expression were significantly induced by oxidative stress , whereas antioxidant had the opposite's effect. Mechanistic investigation manifested that TET2-mediated DNA demethylation promotes the expression of ferroportin and erythroferrone against oxidative stress. Besides, the expression of NRF2 was significantly increased by TET2-mediated DNA demethylation during stress erythropoiesis. Elevated NRF2 expression could also modulate the activation of ferroportin and erythroferrone through a canonical antioxidant response element within its promoter. These direct and indirect pathways of TET2 synergistically cooperated to mediating iron metabolism during stress erythropoiesis. Our work revealed a critical role of TET2-mediated DNA demethylation against oxidative stress, and provided the molecular mechanisms underlying the epigenetic regulation of iron homeostasis in response to stress erythropoiesis.
研究领域:
血液学
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分子生物学
·
表观遗传学
✓ 已验证
DOI
PubMed
高影响因子
Cell Reports
·
2024
·
IF 7.5
Weigang Wang,Na Yang,Liangliang Wang,Yuanxiang Zhu,Xiao Chu,Weijie Xu,Yawei Li,Yihai Xu,Lina Gao,Beibei Zhang,Guoqiang Zhang,Qinmiao Sun,Weihong Wang,Qiang Wang,Wenxin Zhang,Dahua Chen
Craniofacial microsomia (CFM) is a congenital defect that usually results from aberrant development of embryonic pharyngeal arches. However, the molecular basis of CFM pathogenesis is largely unknown. Here, we employ the zebrafish model to investigate mechanisms of CFM pathogenesis. In early embryos, tet2 and tet3 are essential for pharyngeal cartilage development. Single-cell RNA sequencing reveals that loss of Tet2/3 impairs chondrocyte differentiation due to insufficient BMP signaling. Moreover, biochemical and genetic evidence reveals that the sequence-specific 5mC/5hmC-binding protein, Sall4, binds the promoter of bmp4 to activate bmp4 expression and control pharyngeal cartilage development. Mechanistically, Sall4 directs co-phase separation of Tet2/3 with Sall4 to form condensates that mediate 5mC oxidation on the bmp4 promoter, thereby promoting bmp4 expression and enabling sufficient BMP signaling. These findings suggest the TET-BMP-Sall4 regulatory axis is critical for pharyngeal cartilage development. Collectively, our study provides insights into understanding craniofacial development and CFM pathogenesis.
研究领域:
发育生物学
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分子遗传学
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颅面生物学
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2023
·Vol. 14
·期 2
·1-13
·
IF 9
Liu Nian,Zhang Jianglin,Yan Mingjie,Chen Lihui,Wu Jie,Tao Qian,Yan Bei,Chen Xiang,Peng Cong
Patients with advanced melanoma have shown an improved outlook after anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapeutic efficacy remains a major challenge. Here, our findings showed a significantly increased abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanoma tumors via STAT1/3. We also found that supplementation with α-KG significantly increased the activity of the methylcytosine dioxygenases TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 binding to the PD-L1 promoter was stabilized to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, our results provide novel insight into α-KG’s function in anti-PD1 treatment of melanoma and suggest supplementation with α-KG as a novel promising strategy to improve the efficacy of anti-PD1 therapy.
研究领域:
肿瘤学
·
免疫学
·
表观遗传学
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产品关联
DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
·
2020
·
IF 5.977
Danping Chen,Yang Wang,Jun Chen,Yanfei Zhang,Zong Dai,Xiaoyong Zou
Active DNA demethylation process critically relies on the intrinsic properties of ten-eleven translocation proteins (Tets), particularly the flanking sequence preference. Challenged by the fact that the proximate bases to the 5-methylcytosine (5mC) are multitudinous and their influence on the Tets/DNA interplay is minute, the current methodologies are very limited in terms of cost, sensitivity and efficiency. Herein, we propose a polymerization retardation isothermal amplification (PRIA) strategy that enables sensitive and fast study of the flanking sequence preference of Tet. By arranging DNA polymerase to repetitively pass DNA strands through an isothermal replication-scission amplification reaction, the tiny difference in the Tet/DNA interplay can be consecutively accumulated and amplified. Low amount sample (80 ng) even multiple samples can be simultaneously analyzed within 10 h on an easily accessible laboratory real-time quantitative PCR instrument. For a proof-of-concept study, the binding preference ( P B ) of Tet2 for XmCGX, (X = C, G, T , A) was analyzed by PRIA and computational analysis, showing an order of AmCGT > TmCGA ≈ GmCGC > CmCGG. Furthermore, the binding and oxidation preference in Tet/DNA interplay process was individually considered. By comparative evaluation of the total flanking sequence preference ( P T ) and the P B , for the first time, we revealed that Tet2 has a lower oxidation preference ( P O ) to proximal flanking bases and the main contributor to P T of Tet2 is P B . The PRIA strategy, due to its reliable, cost-effective, high efficiency and low sample input, would hopefully advance epigenetic researches and other relative studies.
研究领域:
分子生物学
·
表观遗传学
·
生物化学
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DOI
PubMed
高影响因子
Research
·
2022
·
IF 11.036
Yanhong Wang,Fangchao Xue,Yanzhao Li,Lin Lin,Yeqin Wang,Shanlan Zhao,Xingli Zhao,Yong Liu,Ju Tan,Gang Li,Haoran Xiao,Juan Yan,Hao Tian,Min Liu,Qiao Zhang,Zhaojing Ba,Lang He,Wenyan Zhao,Chuhong Zhu,Wen Zeng
Rapid integration into the host tissue is critical for long-term patency after small diameter tissue engineering vascular grafts (sdTEVGs) transplantation. Neural recognition may be required for host integration and functionalization of the graft. However, immune rejection and inflammation hinder nerve regeneration of sdTEVGs. Here, a CRISPR/dCas9-nanocarrier was used for targeted programming of regulatory T cells (Treg cells) in situ to promote nerve regeneration of sdTEVGs by preventing excessive inflammation. Treg cells and (C-C chemokine receptor) CCR2+ macrophage recruitment occurred after transplantation. The nanodelivery system upregulated ten eleven translocation (TET2) in Treg cells in vitro. Reprogrammed Treg cells upregulated anti-inflammatory cytokines and decreased the proportion of CCR2+ macrophages. IL-6 concentrations decreased to the levels required for nerve regeneration. Implantation of CRISPR/dCas9 nanodelivery system-modified sdTEVGs in rats resulted in Treg cell editing, control of excessive inflammation, and promoted nerve regeneration. After 3 months, nerve regeneration was similar to that observed in normal blood vessels; good immune homeostasis, consistency of hemodynamics, and matrix regeneration were observed. Neural recognition promotes further integration of the graft into the host, with unobstructed blood vessels without intimal hyperplasia. Our findings provide new insights into vascular implant functionalization by the host.
研究领域:
生物医学工程
·
免疫学
·
组织工程
·
分子生物学
·
纳米技术
✓ 已验证
DOI
PubMed
高影响因子
Materials Horizons
·
2025
·
IF 10.7
Linlin Zhao,Meiyu Hu,Xiaohang Yin,Hao Yang,Liyun Zhu,Pingyuan Sun,Xiya Wang,Songwei Ai,Yonghui Zheng,Genjie Li,Tingting Yang,Xuerui Chen,Jingyu Zhang
Effectively alleviating cerebral ischemia-reperfusion (I/R) injury is challenging despite medical advances. Prompt restoration of blood flow after ischemic stroke causes secondary damage to brain tissue, triggers neuroinflammation and overproduces reactive oxygen species (ROS). MiRNA regulates genes involved in neuron apoptosis and neuroinflammation, thus exhibiting potential in ameliorating cerebral I/R injury. However, as miRNA is vulnerable to degradation, its effective delivery poses obstacles to clinical applications. Inspired by therapeutic potential of miR-210 inhibitors in ischemic stroke-induced neuroinflammation, we constructed a multifunctional nanosystem composed of ceria nanozymes and zeolitic imidazolate framework-90 (ZIF-90) nanoparticles to deliver miR-210 inhibitors to treat cerebral I/R injury. Attributed to proton sponge effect of ZIF-90, this nanosystem allows for lysosome escape of miR-210 inhibitors to protect their intracellular bioactivity, while integration of ZIF-90 and ceria nanozymes utilizes multi-enzyme cascade activities to constrain lipid peroxidation and reduce oxidative damage in brain tissues of mice with middle cerebral artery occlusion (MCAO). After crossing the blood-brain barrier, miR-210 inhibitors target TET2 to suppress pro-inflammatory cytokines, finally inhibiting neuroinflammation. More than uncertain stability and efficacy of direct TET2 protein administration, delivery of miR-210 inhibitors by multifunctional nanosystems engendered neuroprotection, indicating their potential for protein replacement therapy against cerebral I/R injury.
研究领域:
神经科学
·
纳米技术
·
分子生物学
·
药剂学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioengineered
·
2022
·
IF 6.832
Fan-Cheng Kong,Li-Qin Lang,Jie Hu,Xia-Ling Zhang,Ming-Kang Zhong,Chun-Lai Ma
Drug-resistant epilepsy (DRE) is a chronic condition derived from spontaneous changes and regulatory effects in the epileptic brain. As demethylation factors, ten-eleven translocation (TET) family members have become a focus in recent studies of neurological disorders. Here, we quantified and localized TET1, TET2 and 5-hydroxymethylcytosine (5-hmC) in the temporal lobe cortex of DRE patients (n = 27) and traumatic brain hemorrhage controls (n = 10) by immunochemical staining. TET2 and ATP binding cassette subfamily B member 1 (ABCB1) expression patterns were determined in the isolated brain capillaries of DRE patients. TET2 expression was significantly increased in the temporal cortical tissue of DRE patients with or without hippocampal sclerosis (HS) compared to control patients, while TET1 and 5-hmC showed no differences in expression. We also found that a particularly strong expression of TET2 in the vascular tissue of DRE patients. ABCB1 and TET2 have evidently higher expression in the vascular endothelium from the neocortex of DRE patients. In blood–brain barrier (BBB) model, TET2 depletion can cause attenuated expression and function of ABCB1. Data from a cohort study and experiments in a BBB model suggest that TET2 has a specific regulatory effect on ABCB1, which may serve as a potential mechanism and target in DRE.
研究领域:
神经病学
·
表观遗传学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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