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The m^(6)A regulator KIAA1429 stabilizes RAB27B mRNA and promotes the progression of chronic myeloid leukemia and resistance to targeted therapy

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Genes & Diseases 2024年第2期11卷 993-1008页

作者： Fangyi Yao Fangmin Zhong Junyao Jiang Ying Cheng Shuai Xu Jing Liu Jin Lin Jing Zhang Shuqi Li Meiyong Li Yanmei Xu Bo Huang Xiaozhong Wang Jiangxi Province Key laboratory of laboratory medicine Jiangxi Provincial Clinical Research Center for Laboratory MedicineDepartment of Clinical LaboratoryThe Second Affiliated Hospital of Nanchang UniversityNanchangJiangxi 330006China

Chronic myeloid leukemia(CML)is a common adult *** the acute phase of the disease and the adverse effects of anti-cancer treatments can lead to a poor *** N6-methyladenine(m^(6)A)modification plays an important regulatory role in various physiological and pathological ***1429 is a known m^(6)A regulator,but the biological role of KIAA1429 in CML is *** this study,we observed that the m^(6)A levels and KIAA1429 expression were significantly up-regulated in patients with blast phase ***,KIAA1429 regulated the total level of RNA m^(6)A modification in the CML cells and promoted the malignant biological behaviors of CML cells,including proliferation,migration,and imatinib *** KIAA1429 in CML cells reduced the stability of RAB27B mRNA through the m^(6)A/YTHDF1 axis,consequently inhibiting CML proliferation and drug efflux,ultimately increasing the sensitivity of CML cells to ***,the knockdown of RAB27B also inhibited the proliferation and drug resistance of CML cells and promoted their ***,a recently developed anti-cancer agent,suppressed the expression of KIAA1429 and CML cell proliferation and promoted cell *** also inhibited the tumorigenesis of CML cells in *** combined use of rucaparib and imatinib enhanced the sensitivity of CML cells to *** study provides evidence that elevated KIAA1429 expression in the blast phase of CML enhances the stability of RAB27B mRNA through the m^(6)A/YTHDF1 axis to up-regulate RAB27B expression,thereby promoting CML *** exerts inhibitory effects on KIAA1429 expression and thus reduces CML progression.

关键词： Chronic myeloid leukemia KIAA1429 N6-methyladenine RAB27B Rucaparib YTHDF1

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Syrosingopine,an anti-hypertensive drug and lactate transporter(MCT1/4)inhibitor,activates hepatic stellate cells and exacerbates liver fibrosis in a mouse model

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Genes & Diseases 2024年第4期11卷 28-30页

作者： Meichun Guo Yannian Gou Xiangyu Dong Jiamin Zhong Aohua Li Ailing Hao Tongchuan He Jiaming Fan Ministry of Education Key laboratory of Diagnostic medicine and the School of Laboratory Diagnostic MedicineChongqing Medical UniversityChongqing 400016China Molecular Oncology laboratory Department of Orthopaedic Surgery and Rehabilitation MedicineThe University of Chicago Medical CenterChicagoIL 60637USA

Syrosingopine is an anti-hypertensive drug and can cause high intracellular lactate levels and end-product inhibition of lactate dehydrogenase by inhibiting the lactate transporters MCT1 and *** studies have shown that syrosingopine plays an essential role in the process of glycolytic blockade,ATP depletion,and cell death in cancer due to high intracellular levels of lactate.

关键词： hypertensive MCT1 drug

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Lactate regulates major zygotic genome activation by H3K18 lactylation in mammals

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National Science Review 2024年第2期11卷 124-134页

作者： Jingyu Li Weibo Hou Qi Zhao Wei Han Hongdi Cui Songling Xiao Ling Zhu Jiadan Qu Xiaoyu Liu Weitao Cong Jingling Shen Yuzheng Zhao Shaorong Gao Guoning Huang Qingran Kong Chongqing Key laboratory of Human Embryo Engineering Center for Reproductive Medicine Chongqing Health Center for Women and ChildrenWomen and Children's Hospital of Chongqing Medical University Oujiang laboratory Zhejiang Provincial Key Laboratory of Medical Genetics Key Laboratory of Laboratory MedicineMinistry of EducationSchool of Laboratory Medicine and Life Sciences Wenzhou Medical University Frontier Science center for Stem Cell Research School of Life Sciences and Technology Tongji University School of Pharmaceutical Science Wenzhou Medical University Institute of Life Sciences College of Life and Environmental Sciences Wenzhou University Optogenetics&Synthetic Biology Interdisciplinary Research center State Key Laboratory of Bioreactor Engineering Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism School of Pharmacy East China University of Science and Technology

Lactate is present at a high level in the microenvironment of mammalian preimplantation embryos in vivo and in vitro. However, its role in preimplantation development is unclear. Here, we report that lactate is highly enriched in the nuclei of early embryos when major zygotic genome activation(ZGA) occurs in humans and mice. The inhibition of its production and uptake results in developmental arrest at the 2-cell stage, major ZGA failure, and loss of lactate-derived H3K18lac, which could be rescued by the addition of Lac-Co A and recapitulated by overexpression of H3K18R mutation. By profiling the landscape of H3K18lac during mouse preimplantation development, we show that H3K18lac is enriched on the promoter regions of most major ZGA genes and correlates with their expressions. In humans, H3K18lac is also enriched in ZGA markers and temporally concomitant with their expressions. Taken together, we profile the landscapes of H3K18lac in mouse and human preimplantation embryos, and demonstrate the important role for H3K18lac in major ZGA, showing that a conserved metabolic mechanism underlies preimplantation development of mammalian embryos.

关键词： mammalian preimplantation development lactate epigenetic remodeling histone lactylation zygotic genome activation

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Allelic reprogramming of chromatin states in human early embryos

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National Science Review 2024年第03期11卷 58-71页

作者： Shenli Yuan Lei Gao Wenrong Tao Jianhong Zhan Gang Lu Jingye Zhang Chuanxin Zhang Lizhi Yi Zhenbo Liu Zhenzhen Hou Min Dai Han Zhao Zi-Jiang Chen Jiang Liu Keliang Wu center for Reproductive medicine Shandong University CAS Key laboratory of Genome Sciences and Information Collaborative Innovation Center of Genetics and Development Beijing Institute of Genomicsand China National Center for BioinformationChinese Academy of Sciences University of Chinese Academy of Sciences CUHK-SDU Joint laboratory on Reproductive Genetics School of Biomedical Sciences the Chinese University of Hong Kong Key laboratory of Reproductive Endocrinology of the Ministry of Education Shandong University center for Reproductive medicine Ren Ji Hospital School of Medicine Shanghai Jiao Tong University CAS center for Excellence in Animal Evolution and Genetics Chinese Academy of Sciences

The reprogramming of parental epigenomes in human early embryos remains elusive. To what extent the characteristics of parental epigenomes are conserved between humans and mice is currently unknown. Here,we mapped parental haploid epigenomes using human parthenogenetic and androgenetic embryos. Human embryos have a larger portion of genome with parentally specific epigenetic states than mouse *** allelic patterns of epigenetic states for orthologous regions are not conserved between humans and mice. Nevertheless, it is conserved that maternal DNA methylation and paternal H3K27me3 are associated with the repression of two alleles in humans and mice. In addition, for DNA-methylation-dependent imprinting, we report 19 novel imprinted genes and their associated germline differentially methylated regions. Unlike in mice, H3K27me3-dependent imprinting is not observed in human early ***, allele-specific epigenomic reprogramming is different in humans and mice.

关键词： human embryo epigenetics reprogramming DNA methylation H3K27me3 chromatin accessibility

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Impact of short-term ambient air pollution exposure on the risk of severe COVID-19

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Journal of Environmental Sciences 2024年第1期135卷 610-618页

作者： Baihuan Feng Jiangshan Lian Fei Yu Dan Zhang Weizhen Chen QiWang Yifei Shen Guoliang Xie Ruonan Wang Yun Teng Bin Lou Shufa Zheng Yida Yang Yu Chen Department of laboratory medicine The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310000China Key laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province Hangzhou 310000China Institute of laboratory medicine Zhejiang UniversityHangzhou 310000China Department of Infectious Diseases The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310000China State Key laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious Diseasesthe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310000China

Ecological studies suggested a link between air pollution and severe COVID-19 outcomes,while studies accounting for individual-level characteristics are *** the present study,we aimed to investigate the impact of short-term ambient air pollution exposure on disease severity among a cohort of 569 laboratory confirmed COVID-19 patients admitted to designated hospitals in Zhejiang province,China,from January 17 to March 3,2020,and elucidate the possible biological processes involved using *** with mild cases,severe cases had higher proportion of medical conditions as well as unfavorable results in most of the laboratory tests,and manifested higher air pollution exposure *** exposure to air pollutants was associated with increased risk of severe COVID-19 with odds ratio(OR)of 1.89(95%confidence interval(CI):1.01,3.53),2.35(95%CI:1.20,4.61),2.87(95%CI:1.68,4.91),and 2.01(95%CI:1.10,3.69)for PM_(2.5),PM_(10),NO_(2)and CO,*** for NO_(2)remained significant in two-pollutant models after adjusting for other *** analysis showed 884 differentially expressed genes which mainly were enriched in virus clearance related biological processes between patients with high and low NO_(2)exposure levels,indicating that compromised immune response might be a potential underlying mechanistic *** findings highlight the impact of shortterm air pollution exposure,particularly for NO_(2),on COVID-19 severity,and emphasize the significance in mitigating the COVID-19 burden of commitments to improve air quality.

关键词： Air pollution COVID-19 Severity Transcriptomics Immune response

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Structural basis of negative regulation of CRISPR-Cas7-11 by TPR-CHAT

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2716-2725页

作者： Tian Hong Qinghua Luo Haiyun Ma Xin Wang Xinqiong Li Chongrong Shen Jie Pang Yan Wang Yuejia Chen Changbin Zhang Zhaoming Su Haohao Dong Xiaodi Tang Department of laboratory medicine State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduChina Frontiers Medical center Tianfu Jincheng LaboratoryWest China HospitalSichuan UniversityChengduChina

CRISPR‒Cas7-11 is a Type Ⅲ-E CRISPR-associated nuclease that functions as a potent RNA editing ***-peptide repeat fused with Cas/HEF1-associated signal transducer(TPR-CHAT)acts as a regulatory protein that interacts with CRISPR RNA(crRNA)-bound Cas7-11 to form a CRISPR-guided caspase complex(Craspase).However,the precise modulation of Cas7-11’s nuclease activity by TPR-CHAT to enhance its utility requires further ***,we report cryo-electron microscopy(cryo-EM)structures of Desulfonema ishimotonii(Di)Cas7-11-crRNA,complexed with or without the full length or the N-terminus of *** structures unveil the molecular features of the Craspase *** analysis,combined with in vitro nuclease assay and electrophoretic mobility shift assay,reveals that DiTPR-CHAT negatively regulates the activity of DiCas7-11 by preventing target RNA from binding through the N-terminal 65 amino acids of DiTPR-CHAT(DiTPR-CHAT_(NTD)).Our work demonstrates that DiTPRCHAT_(NTD) can function as a small unit of DiCas7-11 regulator,potentially enabling safe applications to prevent overcutting and offtarget effects of the CRISPR‒Cas7-11 system.

关键词： CRISPR crRNA TPR

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Sodium Sulfite as a Novel Hypoxia Revulsant Involved in Hypoxic Regulation in Escherichia coli

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Biomedical and Environmental Sciences 2024年第2期37卷 228-232页

作者： YE Qiao HUO Jia Nan LUO Yuan MEI Zhu Song FANG Long Mei GUO Bing Qian WANG Guang Yun laboratory of clinical medicine Air Force Medical CenterAir Force Medical UniversityBeijing 100142China

As a reducing salt,sodium sulfite could deprive oxygen in solution,which could mimic hypoxic stress in Caenorhabditis *** this study,the wildtype Escherichia coli strain MG1655 was used to examine the inhibition of so... 详细信息

关键词： hypoxic Sodium observing

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Development and Characterization of Novel FAP-Targeted Theranostic Pairs: A Bench-to-Bedside Study

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Research 2024年第3期2023卷 473-485页

作者： Wei Huang Yizhen Pang Qiufang Liu Chenyi Liang Shuxian An Qianyun Wu You Zhang Gang Huang Haojun Chen Jianjun Liu Weijun Wei Department of Nuclear medicine Institute of Clinical Nuclear MedicineRenj HospitalSchool of Medicine Shanghai Jiao Tong UniversityShanghai 200127China Department of Nuclear medicine and Minnan PET center Xiamen Cancer CenterXiamen Key Laboratory of Radiation OncologyThe First Affiliated Hospital of Xiamen UniversitySchool of MedicineXiamen UniversityXiamen 361003China Department of Nuclear medicine Fudan University Shanghai Cancer CenterFudan UniversityShanghai 200032China

Fibroblast activation protein (FAP) is among the most popular targets in nuclear medicine imaging and cancer theranostics. Several small-molecule moieties (FAPI-04, FAPI-46, etc.) are used for developing FAP-targeted theranostic agents. Nonetheless, the circulation time of FAP inhibitors is relatively short, resulting in rapid clearance via kidneys, low tumor uptake, and associated unsatisfactory treatment efficacy. To address the existing drawbacks, we engineered 3 peptides named FD1, FD2, and FD3 with different circulation times through solid-phase peptide synthesis. All the 3 reported peptides bind to human and murine FAP with single-digit nanomolar affinity measured by surface plasmon resonance. The diagnostic and therapeutic potential of the agents labeled with 68Ga and 177Lu was assessed in several tumor models exhibiting different levels of FAP expression. While radiolabeled FD1 was rapidly excreted from kidneys, radiolabeled FD2/FD3 have significantly prolonged circulation, increased tumor uptake, and decreased kidney accumulation. Our findings indicated that [68Ga]Ga-DOTA-FD1 positron emission tomography (PET) effectively detected FAP dynamics, whereas [177Lu]Lu-DOTA-FD2 and [177Lu]Lu-DOTA-FD3 exhibited remarkable therapeutic efficacy in FAP-overexpressing tumor models, including pancreatic cancer cell models characterized by abundant stroma. Moreover, a pilot translational investigation demonstrated that [68Ga]Ga-DOTA-FD1 had the capability to identify both primary and metastatic tumors with precision and distinction. In summary, we developed [68Ga]Ga-DOTA-FD1 for same-day PET imaging of FAP dynamics and [177Lu]Lu-DOTA-FD2 and [177Lu]Lu-DOTA-FD3 for effective radioligand therapy of FAP-overexpressing tumors.

关键词： DOTA expressing labeled

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Targeting stroma and tumor,silencing galectin 1 treats orthotopic mouse hepatocellular carcinoma

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Acta Pharmaceutica Sinica B 2024年第1期14卷 292-303页

作者： Tahereh Setayesh Ying Hu Farzam Vaziri Xin Chen Jinping Lai Dongguang Wei Yu-Jui Yvonne Wan Department of Medical Pathology and laboratory medicine University of CaliforniaDavisSacramentoCA 95817USA Cancer Biology Program the University of Hawaii Cancer CenterHonoluluHI 96813USA Department of Pathology and laboratory medicine Kaiser Permanente Sacramento Medical CenterSacramentoCA 95825USA

This study examines inhibiting galectin 1(Gal1)as a treatment option for hepatocellular carcinoma(HCC).Gal1 has immunosuppressive and cancer-promoting *** data showed that Gal1 was highly expressed in human and mouse *** levels of Gal1 positively correlated with the stages of human HCC and negatively with *** roles of Gal1 in HCC were studied using overexpression(OE)or silencing using Igals1 siRNA delivered by *** to HCC initiation induced by RAS and AKT mutations,lgals1-OE and silencing had opposite impacts on tumor *** treatment effect of lgals1 siRNAwas further demonstrated by intersecting HCC at different time points when the tumor load had already reached 9%or even 42%of the body *** spatial transcriptomic profiles of Gal1 silenced and OE HCC,inhibiting matrix formation and recognition of foreign antigen in CD45t cell-enriched areas located at tumor-margin likely contributed to the anti-HCC effects of Gal1 *** the tumors,silencing Gal1 inhibited translational initiation,elongation,and ***,Gal1 silencing increased immune cells as well as expanded cytotoxic T cells within the tumor,and the anti-HCC effect of lgals1 siRNAwas ***,Gal1 silencing has a promising potential for HCC treatment.

关键词： Liver Hepatocellular carcinoma Carbohydrate-binding lectin Galectin 1 Extracellular matrix Translation Spatial transcriptomics Tumor-margin

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OIP5 Interacts with NCK2 to Mediate Human Spermatogonial Stem Cell Self-Renewal and Apoptosis through Cell Cyclins and Cycle Progression and Its Abnormality Is Correlated with Male Infertility

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Research 2024年第1期2023卷 455-469页

作者： Yinghong Cui Wei Chen Li Du Zuping He The Key laboratory of Model Animals and Stem Cell Biology in Hunan Province The Research Center of Reproduction and Translational Medicine of Hunan ProvinceHunan Normal University School of MedicineChangsha 410013HunanChina

Spermatogonial stem cells(SSCs)have important applications in both reproduction and regenerative ***,specific genes and signaling transduction pathways in mediating fate decisions of human SSCs remain ***,we have demonstrated for the first time that OIP5(Opa interacting protein 5)controlled the self-renewal and apoptosis of human *** sequencing identified that NCK2 was a target for OIP5 in human SSCs,and interestingly,OIP5 could interact with NCK2 as shown by Co-IP(co-immunoprecipitation),IP-MS(mass spectrometry),and GST pulldown ***2 silencing decreased human SSC proliferation and DNA synthesis but enhanced their ***,NCK2 knockdown reversed the influence of OIP5 overexpression on human ***,OIP5 inhibition decreased the numbers of human SSCs at S and G2/M phases,while the levels of numerous cell cycle proteins,including cyclins A2,B1,D1,E1 and H,especially cyclin D1,were remarkably ***,whole-exome sequencing of 777 patients with nonobstructive azoospermia(NOA)revealed 54 singlenucleotide polymorphism mutations of the OIP5 gene(6.95%),while the level of OIP5 protein was obviously lower in testes of NOA patients compared to fertile ***,these results implicate that OIP5 interacts with NCK2 to modulate human SSC self-renewal and apoptosis via cell cyclins and cell cycle progression and that its mutation and/or lower expression is correlated with *** such,this study offers novel insights into molecular mechanisms underlying the fate determinations of human SSCs and the pathogenesis of NOA,and it provides new targets for treating male infertility.

关键词： OIP5 Apoptosis reversed

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