eLife
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2021
·
IF 8.146
Chunbo Zhang,Tianyu Zhong,Yuanyuan Li,Xianfeng Li,Xiaopeng Yuan,Linlin Liu,Weilin Wu,Jing Wu,Ye Wu,Rui Liang,Xinhua Xie,Chuanchuan Kang,Yuwen Liu,Zhonghong Lai,Jianbo Xiao,Zhixian Tang,Riqun Jin,Yan Wang,Yongwei Xiao,Jin Zhang,Jian Li,Qian Liu,Zhongsheng Sun,Jianing Zhong
Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is involved in multiple biological functions in cell development, differentiation, and transcriptional regulation. Tet1 deficient mice display the defects of murine glucose metabolism. However, the role of TET1 in metabolic homeostasis keeps unknown. Here, our finding demonstrates that hepatic TET1 physically interacts with silent information regulator T1 (SIRT1) via its C-terminal and activates its deacetylase activity, further regulating the acetylation-dependent cellular translocalization of transcriptional factors PGC-1α and FOXO1, resulting in the activation of hepatic gluconeogenic gene expression that includes PPARGC1A, G6PC, and SLC2A4. Importantly, the hepatic gluconeogenic gene activation program induced by fasting is inhibited in Tet1 heterozygous mice livers. The adenosine 5’-monophosphate-activated protein kinase (AMPK) activators metformin or AICAR—two compounds that mimic fasting—elevate hepatic gluconeogenic gene expression dependent on in turn activation of the AMPK-TET1-SIRT1 axis. Collectively, our study identifies TET1 as a SIRT1 coactivator and demonstrates that the AMPK-TET1-SIRT1 axis represents a potential mechanism or therapeutic target for glucose metabolism or metabolic diseases.
研究领域:
分子生物学
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代谢学
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药理学
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DOI
PubMed
高影响因子
BIOELECTROCHEMISTRY
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2023
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IF 5
Ying Cheng,Chen Chen,Fang Wang,Zilin Chen
Ten-eleven translocation 1 (TET1) is a member of the TET enzyme family of dioxygenases, which plays an important role in active DNA demethylation. Therefore, the sensitive TET1 detection could help us better understand DNA methylation-demethylation in epigenetics. Here we report a detection method that consists of electrode fabrication, TET1 modification, DNA digestion, signal-on oxidoreduction, and current peak monitoring. An exquisitely designed 5′end-G-rich oligodeoxynucleotide was synthesized bearing a methylated cytosine (5-mC), which formed into hairpin dsDNA with the MspI recognition sequence (C m C GG/GGCC). Then hairpin dsDNA was fabricated onto gold nanoparticles modified glassy carbon electrode (DNA/AuNPs/GCE) via Au-S bond. The combination uses of restriction enzyme MspI and hemin converted fabricated-dsDNA into peroxidase-mimicking DNAzyme, thereby promoting the reduction of H 2 O 2 with a current peak. However, the current peak was extremely decreased once TET1 and T4 β-GT were used in advance. We confirmed a delicately linear relationship matching between the current difference and TET1 activity from 0.7 to 10.5 ng μL −1 with a detection limit of 0.027 ng μL −1 , which outcompeted the former methods at least one order of magnitudes. The TET1 activity evaluation in the existence of Bobcat339 was also tested as the proof of concept of inhibitors screening. Our strategy provides a novel, label-free, and sensitive electrochemical approach that enables us to complete both TET1 activity evaluation and potential TET1 inhibitors screening.
研究领域:
生物化学
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分子生物学
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分析化学
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DOI
PubMed
高影响因子
Theranostics
·
2023
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IF 12.4
Yu Fan,Yangmian Yuan,Mingrui Xiong,Muchuan Jin,Donge Zhang,Dong Yang,Chengyu Liu,Robert B. Petersen,Kun Huang,Anlin Peng,Ling Zheng
Rationale: Increased methylation of key genes has been observed in kidney diseases, suggesting that the ten-eleven translocation (Tet) methyl-cytosine dioxygenase family as well as 5mC oxidation may play important roles. As a member of the Tet family, the role of Tet1 in acute kidney injury (AKI) remains unclear. Methods: Tet1 knockout mice, with or without tempol treatment, a scavenger of reactive oxygen species (ROS), were challenged with ischemia and reperfusion (I/R) injury or unilateral ureteral obstruction (UUO) injury. RNA-sequencing, Western blotting, qRT-PCR, bisulfite sequencing, chromatin immunoprecipitation, immunohistochemical staining, and dot blot assays were performed. Results: Tet1 expression was rapidly upregulated following I/R or UUO injury. Moreover, Tet1 knockout mice showed increased renal injury and renal cell death, increased ROS accumulation, G2/M cell cycle arrest, inflammation, and fibrosis. Severe renal damage in injured Tet1 knockout mice was alleviated by tempol treatment. Mechanistically, Tet1 reduced the 5mC levels in an enzymatic activity-dependent manner on the promoters of Sod1 and Sod2 to promote their expression, thus lowering injury-induced excessive ROS and reducing I/R or UUO injury. Conclusions: Tet1 plays an important role in the development of AKI by promoting SOD expression through a DNA demethylase-dependent mechanism.
研究领域:
肾病学
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分子生物学
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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
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2021
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IF 3.935
Ying Cheng,Jing Tang,Xue Chen,Fang Wang,Zilin Chen
Ten-eleven translocation protein 1 (TET1) is one member of TET proteins family which plays a key role in dynamic DNA methylation-demethylation process. Herein, a novel biosensor was constructed for TET1 detection and its inhibitors screening utilizing restriction digestion of endonuclease enzyme MspI. Half-methylated oligonucleotide (5mC DNA) was used as target and Ru(NH 3 ) 6 3+ as electrochemical signal probe. After the treatment by TET1 and T4 β-glucosyltransferase (T4 β-GT), target oligonucleotide would not be recognized and digested. If there was no TET1, the target would be digested and the response of biosensor decreased greatly. The current difference of biosensor with and without the incubation with TET1 was therefore dependent on the concentration of TET1. To increase sensitivity of the biosensor, nanostructured film at electrode surface and nanoparticles modified oligonucleotides were employed as signal amplification elements for Ru(NH 3 ) 6 3+ recycling. Finally, this biosensor showed high performance with a wide linear range of TET1 concentration from 3.5–21 ng/μL and a low detection limit of 0.33 ng/μL, which is superior to other existing methods. The inhibition effects of Bobcat339 on TET1 was successfully proved by our biosensor with an IC 50 of 38 μM. Not only that, but the feasibility of the biosensor for inhibitors screening was evaluated and further confirmed by other compounds including two anticancer drugs and three active ingredients of traditional Chinese medicine.
研究领域:
生物化学
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分子生物学
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分析化学
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DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
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2021
·Vol. 22
·期 4
·1-7
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IF 2.447
Yiyuan Zhou,Fang Zhang,Huijiao Jiang,Di Xu,Dongyang Deng
The present study hypothesized that fumaric acid and succinic acid may exhibit therapeutic effects on gestational hypertension. During pregnancy, estrogen upregulates ten‑eleven translocation 1 (TET1) expression, which subsequently increases calcium‑activated potassium channel subunit β1 (KCNMB1) expression. KCNMB1 is associated with hypertension. Fumaric acid and succinic acid are understood to inhibit TET. Therefore, the present study investigated whether fumaric acid and succinic acid exhibit therapeutic effects on gestational hypertension and whether these effects are mediated by TET1 and KCNMB1. Nω‑Nitro‑L‑arginine methyl ester hydrochloride was injected into rats to establish a gestational hypertension model. Dimethyl fumarate (DMF) and succinic acid were administrated into rats to treat gestational hypertension. Rats were divided into five groups: i) Control; ii) model; iii) DMF; iv) succinic acid; and v) DMF + succinic acid. Blood pressure was monitored by a noninvasive meter and urinary protein was determined using a urinary protein kit. Placenta pathology was examined by hematoxylin‑eosin staining. Compared with the control group, urinary protein and blood pressure in the model group increased significantly. The placental cells in the control group were arranged orderly. However, in the model group, decidual cellular edema of placenta and vacuolar degeneration were observed, and the intervascular membrane was markedly thicker with plenty of fibrin deposition. These results indicate successful establishment of a gestational hypertension model. However, compared with the model group, urinary protein, blood pressure, edema, vacuoles and fibrin deposition were markedly reduced in the DMF, succinic acid and DMF + succinic acid groups. mRNA and protein levels of TET1 and KCNMB1 in placenta were evaluated by immunohistochemical analysis, reverse transcription‑quantitative polymerase chain reaction and western blotting. The TET1 and KCNMB1 levels in the model group were markedly increased compared with those in the control group. However, compared with the model group, the expression levels were markedly downregulated in the DMF, succinic acid and DMF + succinic acid groups. In conclusion, fumaric acid and succinic acid may treat gestational hypertension by downregulating the expression of KCNMB1 and TET1.
研究领域:
药理学
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妇产科学
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分子生物学
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DOI
PubMed
高影响因子
Cell Reports
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2021
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IF 9.423
Wen Chen,Nana Liu,Shijun Shen,Wei Zhu,Jing Qiao,Shujuan Chang,Jianfeng Dong,Mingliang Bai,Li Ma,Shanshan Wang,Wenwen Jia,Xudong Guo,Ang Li,Jiajie Xi,Cizhong Jiang,Jiuhong Kang
Summary Fetal growth restriction (FGR) increases the risk for impaired cognitive function later in life. However, the precise mechanisms remain elusive. Using dexamethasone-induced FGR and protein restriction-influenced FGR mouse models, we observe learning and memory deficits in adult FGR offspring. FGR induces decreased hippocampal neurogenesis from the early post-natal period to adulthood by reducing the proliferation of neural stem cells (NSCs). We further find a persistent decrease of Tet1 expression in hippocampal NSCs of FGR mice. Mechanistically, Tet1 downregulation results in hypermethylation of the Dll3 and Notch1 promoters and inhibition of Notch signaling, leading to reduced NSC proliferation. Overexpression of Tet1 activates Notch signaling, offsets the decline in neurogenesis, and enhances learning and memory abilities in FGR offspring. Our data indicate that a long-term decrease in Tet1/Notch signaling in hippocampal NSCs contributes to impaired neurogenesis following FGR and could serve as potential targets for the intervention of FGR-related cognitive disorders.
研究领域:
发育生物学
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神经科学
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分子生物学
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DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
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2020
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IF 5.977
Zhenya Yu,Xue Chen,Ying Cheng,Hongmei Yang,Fang Wang,Zilin Chen
A label-free electrochemical method was developed for sensitive determination of ten-eleven translocation protein 1 (TET1) which can mediate the demethylation of DNA . This strategy is mainly based on MspI-mediated restriction endonuclease reaction. Current response difference of the biosensor before and after cleavage by MspI was dependent on the activity and concentration of TET1. With the aid of Au nanoparticles , this method shows a good linear range from 0.0042 μg μL −1 to 0.0210 μg μL −1 with a correlation coefficient of 0.9350 and a low limit of detection 0.00098 μg μL −1 . Finally, this method was used to investigate the effects of n-oxalylglycine (NOG) and taxol on activity of TET1. The results indicated that NOG could inhibit TET1 activity but taxol could not. So this electrochemical biosensor could be applied to TET activity evaluation and inhibitor screening in field of biomedicine and clinical diagnosis.
研究领域:
生物医学
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临床诊断
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分子生物学
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DOI
PubMed
高影响因子
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