Advanced Science
·
2024
·
IF 14.3
Jiaxing Huang,Xiaotang Wang,Na Li,Wei Fan,Xingran Li,Qian Zhou,Jiangyi Liu,Wanqian Li,Zhi Zhang,Xiaoyan Liu,Shuhao Zeng,Hui Yang,Meng Tian,Peizeng Yang,Shengping Hou
Activated microglia in the retina are essential for the development of autoimmune uveitis. Yin-Yang 1 (YY1) is an important transcription factor that participates in multiple inflammatory and immune-mediated diseases. Here, an increased YY1 lactylation in retinal microglia within in the experimental autoimmune uveitis (EAU) group is observed. YY1 lactylation contributed to boosting microglial activation and promoting their proliferation and migration abilities. Inhibition of lactylation suppressed microglial activation and attenuated inflammation in EAU. Mechanistically, cleavage under targets & tagmentation （CUT&Tag） analysis revealed that YY1 lactylation promoted microglial activation by regulating the transcription of a set of inflammatory genes, including STAT3, CCL5, IRF1, IDO1 , and SEMA4D . In addition, p300 is identified as the writer of YY1 lactylation. Inhibition of p300 decreased YY1 lactylation and suppressed microglial inflammation in vivo and in vitro. Collectively, the results showed that YY1 lactylation promoted microglial dysfunction in autoimmune uveitis by upregulating inflammatory cytokine secretion and boosting cell migration and proliferation. Therapeutic effects can be achieved by targeting the lactate/p300/YY1 lactylation/inflammatory genes axis.
研究领域:
免疫学
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神经科学
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分子生物学
·
眼科学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-19
·
IF 15.7
Li Wenchao,Chen SaiSai,Lu Jian,Mao Weipu,Zheng Shiya,Zhang Minhao,Wu Tiange,Chen Yurui,Lu Kai,Chu Chunyan,Shu Chuanjun,Hou Yue,Yang Xue,Shi Naipeng,Chen Zhijun,Zhang Lihua,Zhang Lei,Na Rong,Chen Ming,Ju Shenghong,Zhang Dingxiao,Ma Yi,Xu Bin
Immune checkpoint therapy for prostate cancer (PCa), a classic ‘immune-cold’ tumor characterized by an immunosuppressive tumor microenvironment, failed previously in clinical trials, but the underlying causes remain elusive. Here we find that YY1 + , immunosuppressive macrophages aggregate in the hypoxic areas of PCa. Mechanistically, hypoxia promotes the phase separation of YY1 in the nucleus, where YY1 binds to NUSAP1 and promotes the SUMOylation, phase separation and stabilization of HIF-1α. Either myeloid-specific conditional knockout of YY1 or a treatment with tenapanor for decreasing the YY1–NUSAP1–HIF-1α interaction impairs subcutaneous PCa tumor formation in mouse prostate tumor models. Lastly, a first-generation tetrahedral DNA nanostructure based on the proteolysis targeting chimera technique, termed YY1-DcTAC, allows targeting and degrading YY1 in tumor-associated macrophages for inducing antitumor effects and CD8 + T cell tumor infiltration in mouse tumor models. In summary, our findings underscore the pivotal role of YY1 in the hypoxia/HIF-1α pathway in tumor-associated macrophages and support the targeting of YY1 for treating PCa.
研究领域:
肿瘤生物学
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免疫学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
·
2019
·
IF 4.367
Xin-Chun Zhang,Ai-Ping Gu,Chun-Ye Zheng,Ying-Bin Li,Hong-Feng Liang,Hua-Jun Wang,Xia-Lin Tang,Xiao-Xin Bai,Jun Cai
Yin-Yang 1 (YY1) has been identified as playing critical roles in multiple diseases . However, little is known regarding its roles and mechanisms in cerebral ischemia/reperfusion (I/R) injury. This study is aimed to explore the roles of YY1 in regulating neuronal apoptosis in cerebral I/R injury and its underlying mechanisms. Primary mouse cerebral cortical neurons were isolated and subjected to OGD/R to mimic cerebral I/R injury in vitro . The roles of YY1 on OGD/R-induced neuronal injury were investigated by performing western blotting , quantitative real-time polymerase chain reaction, TUNEL , RNA-binding protein immunoprecipitation , chromatin immunoprecipitation, chromatin isolation by RNA purification assay, glucose uptake assay, lactate production assay, and extracellular acidification rate assay. YY1-binding long non-coding RNAs (LncRNAs) in neurons subjected to OGD/R were identified by RIP and RNA sequencing . The roles of YY1 on cerebral I/R in vivo were detected by assessing neuronbehaviour, infarct size, and neuronal apoptosis. We found that YY1 expression is downregulated, and LncRNA GAS5 is upregulated in neurons subjected to OGD/R. OGD/R treatment promotes YY1 interacting with GAS5 in neurons, and YY1 negatively regulates GAS5 expression by binding to GAS5 promoter to repress its transcription. Besides, YY1 and GAS5 bind to the same region of PFKFB3 promoter to promote PFKFB3 expression and strengthen neuronal glycolysis, resulting in aggravating OGD/R-induced neuronal apoptosis. Knockdown of YY1 or GAS5 protects against I/R-induced ischemic brain damage and improves overall neurological functions in vivo. Overall, YY1 interacts with LncRNA GAS5 to promote PFKFB3 transcription to enhance neuronal glycolysis, resulting in aggravating cerebral I/R injury.
研究领域:
神经科学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2018
·
IF 2.559
Xin-Chun Zhang,Hong-Feng Liang,Xiao-Dong Luo,Hua-Jun Wang,Ai-Ping Gu,Chun-Ye Zheng,Qiao-Zhen Su,Jun Cai
Neuroinflammation plays a critical role in the process of neurodegenerative disorders, during which microglia , the principal resident immune cells in the central nervous system, are activated and produce proinflammatory mediators. Yin-Yang 1 (YY1), a multi-functional transcription factor, is widely expressed in cells of the immune system and participate in various cellular processes. However, whether YY1 is involved in the process of neuroinflammation is still unknown. In the present study, we found that YY1 was progressively up-regulated in BV2 microglial cells stimulated with lipopolysaccharide (LPS), which was dependent on the transactivation function of nuclear factor kappa B (NF-κB). Furthermore, YY1 knockdown notably inhibited LPS-induced the activation of NF-κB signaling and interleukin-6 (IL-6) expression in BV-2 cells, but not mitogen-activated protein kinase (MAPK) signaling. Moreover, YY1 strengthened p65 binding to IL-6 promoter by interacting with p65 but decreased H3K27ac modification on IL-6 promoter, eventually increasing IL-6 transcription. Taken together, these results for the first time uncover the regulatory mechanism of YY1 on IL-6 expression during neuroinflammation responses and provide new lights into neuroinflammation.
研究领域:
神经科学
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免疫学
·
分子生物学
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DOI
PubMed
高影响因子
LIFE SCIENCES
·
2024
·
IF 5.2
Qiuwen Fei,Jian Zhang,Liangqiong Chen,Manqi Shi,Qinglan Wang,Feifan Xu,Jiahai Shi,Yongwei Qin
Background Mycobacterium tuberculosis infection triggers various forms of host cell death, including ferroptosis in lung epithelial cells; YY1, a critical transcription factor, plays a pivotal role in regulating ferroptosis, however, the underlying mechanisms are not fully understood. Methods To investigate Mycobacterium marinum ( M.marinum )infection in lung epithelial cells A549 and H1299, we utilized flow cytometry to evaluate cell death and measure reactive oxygen species (ROS). Colony-forming unit (CFU) assays determined the intracellular bacterial load. Ferroptosis was analyzed using a specific detection kit to measure malondialdehyde (MDA) and glutathione (GSH) levels. The interaction between the transcription factor YY1 and the iNOS promoter was assessed through a dual-luciferase reporter assay. Results M.marinum induced ferroptosis in lung epithelial cells through invasion. This effect is most pronounced at 8 h of infection and decreases over time but increased with a higher multiplicity of infection (MOI). YY1 knockdown decreases the expression of SLC7A11 and GPX4, attenuates cellular ferroptosis, while YY1 overexpression has the opposite phenomenon, enhancing the expression of bactericidal molecules such as iNOS and MPEG1, thereby markedly reducing the intracellular bacterial load. We identified substantial binding of YY1 to the iNOS promoter region (−655 to −1018 bp), enhancing mycobactericidal activity in YY1-overexpressing cells. Conclusions Our study demonstrates that YY1 inhibits ferroptosis induced by Mycobacterium marinum infection and reduces intracellular bacterial proliferation in lung epithelial cells. These findings provide a crucial basis for developing anti-tuberculosis therapies that target YY1 modulation, potentially offering new clinical avenues for the treatment of tuberculosis.
研究领域:
微生物学
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细胞生物学
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传染病学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Yuxi Guo,Xuemei Jia,Pengli Du,Jie Wang,Yao Du,Bolin Li,Yucong Xue,Jianming Jiang,Yanru Cai,Qian Yang
Ethnopharmacological relevance Xianglianhuazhuo formula (XLHZ) has a potential therapeutic effect on chronic atrophic gastritis (CAG). However, the specific molecular mechanism remains unclear. Aim of the study To evaluate the effect of XLHZ on CAG in vitro and in vivo and its potential mechanisms. Methods A rat model of CAG was established using a composite modeling method, and the pathological changes and ultrastructure of gastric mucosa were observed. YY1/miR-320a/TFRC and ferroptosis-related molecules were detected. An MNNG-induced gastric epithelial cell model was established in vitro to evaluate the inhibitory effect of XLHZ on cell ferroptosis by observing cell proliferation, migration, invasion, apoptosis, and molecules related to ferroptosis. The specific mechanism of action of XLHZ in treating CAG was elucidated by silencing or overexpression of targets. Results In vivo experiments showed that XLHZ could improve the pathological status and ultrastructure of gastric mucosa and inhibit ferroptosis by regulating the YY1/miR-320a/TFRC signaling pathway. The results in vitro demonstrated that transfection of miR-320a mimics inhibited cell proliferation, migration, and invasion while promoting cell apoptosis. MiR-320a targeted TFRC and inhibited ferroptosis. Overexpression of TFRC reversed the inhibitory effect of miR-320a overexpression on cell proliferation. The effect of XLHZ was consistent with that of miR-320a. YY1 targeted miR-320a, and its overexpression promoted ferroptosis. Conclusion XLHZ inhibited ferroptosis by regulating the YY1/miR-320a/TFRC signaling pathway, ultimately impeding the progression of CAG.
研究领域:
民族药理学
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分子生物学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2026
·Vol. 27
·期 10
·4593
·
IF 5.6
Xiaolin Zhang,Yushan Du,Penghui Yang,Shiji Li,Fengya Cui,Xinran Li,Xinyue Du,Bingyao Sun,Yulu Ma,Wenjie Sui,Min Zhang,Jing Meng
Type II diabetes mellitus (T2DM), a chronic metabolic disorder characterized by insulin resistance, is often accompanied by dysregulated bile acid metabolism. Although gastrodin, a bioactive compound derived from Gastrodia elata, has demonstrated potential in diabetes management, its therapeutic mechanisms remain incompletely understood. The aim of this study is to investigate the therapeutic effects and potential mechanisms of gastrodin on T2DM mice from the perspective of bile acid metabolism. In this study, we found that gastrodin could not only reduce lipid accumulation, reduce inflammation, improve antioxidant capacity, alleviate oxidative stress, change the composition of intestinal flora, and improve the disorder of flora caused by the disease in T2DM mice, but also target Yin yang 1 (YY1) to reduce the expression level of YY1 in the liver under a high-fat diet condition. At the same time, YY1 negatively regulates the expression level of Farnesoid X Receptor (FXR), which increases the expression level of FXR, inhibits the enzyme activity of Cholesterol-7α-hydroxylase (CYP7A1) through Small Heterodimer Partner (SHP), reduces the production of chenodeoxycholic acid (CDCA) in the liver, and further affects the production of secondary bile acids through liver–intestinal circulation, promoting the secretion of Glucagon-Like Peptide-1 (GLP-1) and insulin, thereby reducing blood glucose. At the same time, combined with the results of HE staining, gastrodin can reduce the pathological damage of the liver and pancreas in type II diabetic mice, repairing their normal morphology and function. It provides a direct pathological basis for the improvement of diabetes and liver complications, provides theoretical support for the subsequent research and development of precision targeted drugs, provides experimental basis for the development of new natural hypoglycemic drugs, and promotes the transformation and application of the modernization of traditional Chinese medicine in the field of metabolic diseases.
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DOI
PubMed
高影响因子
Stem Cell Research
·
2016
·
IF 3.892
Min Jin,Yutao Wu,Yanwei Wang,Danqing Yu,Mei Yang,Feng Yang,Chun Feng,Ting Chen
MicroRNA-29a (miR-29a) has been extensively studied in tumor biology and fibrotic diseases, but little is known about its functional roles in vascular smooth muscle cell (VSMC) differentiation from embryonic stem cells (ESCs). Using well-established VSMC differentiation models, we have observed that miR-29a induces VSMC differentiation from mouse ESCs by negatively regulating YY1, a transcription factor that inhibits muscle cell differentiation and muscle-specific gene expression. Moreover, gene expression levels of three VSMC specific transcriptional factors were up-regulated by miR-29a over-expression, but down-regulated by miR-29a inhibition or YY1 over-expression. Taken together, our data demonstrate that miR-29a and its target gene, YY1, play a regulatory role in VSMC differentiation from ESCs in vitro and in vivo .
研究领域:
分子生物学
·
干细胞研究
·
心血管生物学
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DOI
PubMed
高影响因子
NUCLEIC ACIDS RESEARCH
·
2022
·Vol. 50
·期 9
·4917-4937
·
IF 19.16
Wang Wenmeng,Qiao Shiyao,Li Guangyue,Cheng Jiahui,Yang Cuicui,Zhong Chen,Stovall Daniel B,Shi Jinming,Teng Chunbo,Li Dangdang,Sui Guangchao
As an oncogenic transcription factor, Yin Yang 1 (YY1) regulates enhancer and promoter connection. However, gaps still exist in understanding how YY1 coordinates coactivators and chromatin enhancer elements to assemble enhancers and super-enhancers. Here, we demonstrate that a histidine cluster in YY1’s transactivation domain is essential for its formation of phase separation condensates, which can be extended to additional proteins. The histidine cluster is also required for YY1-promoted cell proliferation, migration, clonogenicity and tumor growth. YY1-rich nuclear puncta contain coactivators EP300, BRD4, MED1 and active RNA polymerase II, and colocalize with histone markers of gene activation, but not that of repression. Furthermore, YY1 binds to the consensus motifs in the FOXM1 promoter to activate its expression. Wild-type YY1, but not its phase separation defective mutant, connects multiple enhancer elements and the FOXM1 promoter to form an enhancer cluster. Consistently, fluorescent in situ hybridization (FISH) assays reveal the colocalization of YY1 puncta with both the FOXM1 gene locus and its nascent RNA transcript. Overall, this study demonstrates that YY1 activates target gene expression through forming liquid-liquid phase separation condensates to compartmentalize both coactivators and enhancer elements, and the histidine cluster of YY1 plays a determinant role in this regulatory mechanism.
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DOI
PubMed
高影响因子
MOLECULAR CELL
·
2025
·
IF 16.6
Lu-ning Qin,Ting Wu,Xue-ting Zhen,Yun-long Zhao,Jie-shi Zhou,Shan-bin Cheng,Kai-wen Wang,Shuai Qiao,Ding-zhi Huang,Heng Zhang,Tao Sun
The link between extrachromosomal DNA (ecDNA) and tumors has been well established, and its role in cancer is of increasing interest. While ecDNA is thought to originate from genomic instability, the molecular mechanisms driving DNA end ligation during ecDNA formation and the regulatory factors controlling its selective gene packaging remain unresolved. Here, using the multi-layer perceptron model, a series of imaging strategies in human cancer cells, and clinical chip verification, we demonstrate that ecDNA biogenesis depends on transcription factor Yin Yang 1 (YY1)-mediated DNA looping coupled with religation catalyzed by DNA ligase 3 (Lig3), a mechanism that extends existing models. Notably, PARylation-dependent acidic microenvironments mediated by the Lig3-YY1 complex play a critical role in the formation of Z-DNA, which potentially facilitates the fusion-religation process to drive ecDNA biogenesis. Furthermore, our findings establish PARP inhibitors as specific agents for ecDNA-targeted strategies in cancer therapy.
研究领域:
分子生物学
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遗传学
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癌症生物学
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生物信息学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Human Cell
·
2022
·Vol. 35
·期 5
·1535-1546
·
IF 4.374
Mao Dong,Zhang Xiaowei,Wang Zhaoping,Xu Guannan,Zhang Yun
Transmembrane protein 97 (TMEM97) is a conserved integral membrane protein highly expressed in various human cancers, including colorectal cancer (CRC), and it exhibits pro-tumor roles in breast cancer, gastric cancer, and glioma. However, whether TMEM97 participates in CRC progression is not fully understood. The expression of mRNA and protein was evaluated by real-time qPCR, western blotting, immunofluorescent, and immunohistochemical staining. TMEM97 functions in cell proliferation, apoptosis, migration, and invasion were assessed by CCK-8, flow cytometry, and transwell assays. The roles of TMEM97 in CRC cells in vivo was investigated using a subcutaneous xenograft model. The transcriptional regulation of TMEM97 was explored by luciferase reporter and ChIP assays. The silencing of TMEM97 inhibited migration and invasion of CRC cells in vitro and led to suppressed growth and enhanced apoptosis in CRC cells and xenografts, whereas overexpression of TMEM97 displayed opposite effects. Mechanistically, TMEM97 knockdown caused a reduction of the proliferating marker PCNA and an increase of pro-apoptotic proteins (cleaved caspase 8/3/7 and cleaved PARP) in CRC cells. TMEM97 also positively regulated the β-catenin signaling pathway in CRC cells and xenografts by modulating the phosphorylated-GSK-3β and active (non-phospho) β-catenin levels. Interestingly, YY1, a well-recognized oncogenic transcription factor, was identified to bind to the TMEM97 promoter and enhance its transcriptional activity, and silencing of TMEM97 abolished YY1-mediated pro-tumor effects on CRC cells. Our results suggest that TMEM97 is transcriptionally activated by YY1 and promotes CRC progression via the GSK-3β/β-catenin signaling pathway, providing that TMEM97 might be a novel therapeutic target for preventing CRC development.
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产品关联
DOI
PubMed
高影响因子
CURRENT NEUROVASCULAR RESEARCH
·
2023
·Vol. 20
·期 4
·480-492
·
IF 2.1
Li Xuejing,Wang Ying,Zhou Xiang,Wang Hui,Xu Jiang
Background: Increasing evidence shows that electroacupuncture pretreatment (EP) plays a crucial role in cerebral ischemia-reperfusion (I/R) injury, and cerebral I/R injury is the most serious complication of ischemic stroke treatment. The role of miR-155-5p in cerebral I/R injury has
been studied, but the regulation of EP on miR-155-5p has not been reported.Methods: The middle cerebral artery occlusion (MCAO) mice were used to investigate the role of EP in cerebral I/R injury. Longa and modified neurological severity scores (mNSS) were used to evaluate neurological
impairment. HE staining and TUNEL staining were used to evaluate brain injury. The expressions of miR-155-5p, Yin Yang 1 (YY1) and p53 were detected by qRT-PCR. The expressions of related proteins were detected by western blot. The binding of YY1 to miR- 155-5p was verified by dual-luciferase
reporter assay and chromatin immunoprecipitation (ChIP) assay. Mice brain microvascular endothelial cells (BMECs) were isolated and cultured for in vitro experiments. Oxygen-glucose deprivation/reoxygenation (OGD/R) was used to verify the role of YY1, p53 and miR-155-5p in cerebral I/R injury
in vitro.Results: MCAO modeling induced brain injury, apoptosis, and increased levels of miR-155-5p, YY1, and p53. EP markedly alleviated brain injury and reduced levels of miR-155-5p, p53, and YY1. miR-155 agomir markedly increased the expression of miR-155-5p and p53. miR-155 antagomir
decreased the levels of miR-155-5p and p53. Dual-luciferase reporter and ChIP assay verified that YY1 regulated miR-155-5p expression. YY1 shNRA greatly decreased miR-155-5p and p53. Inhibition of p53 decreased miR-155-5p expression. Both miR-155-5p inhibitor and YY1 shRNA promoted proliferation,
inhibited apoptosis, and decreased levels of ICAM-1 and Eselectin of OGD/R-treated BMECs. Inhibition of p53 strengthened the effect of miR-155-5p inhibitor and YY1 shNRA on BMECs.Conclusion: Electroacupuncture pretreatment alleviates cerebral ischemia-reperfusion injury by regulating the
YY1/p53/miR-155-5p axis.
研究领域:
神经科学
·
分子生物学
·
针灸
·
脑血管疾病
✓ 已验证
DOI
PubMed
高影响因子
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