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Clinical applications of the CRISPR/Cas9 genome-editing system: Delivery options and challenges in precision medicine

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Genes & Diseases 2024年第1期11卷 268-282页

作者： Mohadeseh Khoshandam Hossein Soltaninejad Marziyeh Mousazadeh Amir Ali Hamidieh Saman Hosseinkhani Department of Reproductive biology Academic Center for EducationCultureand Research(ACECR)Qom BranchQom ***Iran National Institute of Genetic Engineering and Biotechnology(NIGEB) Tehran 14155-6463Iran Faculty of Interdisciplinary Science and Technology Tarbiat Modares UniversityTehran 14117-13116Iran Pediatric cell and Gene Therapy Research center GeneCell&Tissue Research InstituteTehran UniversityofMedical SciencesTehran14155-6559Iran Department of Nanobiotechnology Faculty of Biological SciencesTarbiat Modares UniversityTehran 14117-13116Iran Department of Biochemistry Faculty of Biological SciencesTarbiat Modares UniversityTehran 14117-13116Iran

CRISPR/Cas9 is an effective gene editing tool with broad applications for the pre-vention or treatment of numerous *** depends on CRiSPR(clustered regularly inter-spaced short palindromic repeats)as a bacterial immune system and plays as a gene editing *** to the higher specificity and efficiency of CRISPR/Cas9 compared to other editing ap-proaches,it has been broadly investigated to treat numerous hereditary and acquired ill-nesses,including cancers,hemolytic diseases,immunodeficiency disorders,cardiovascular diseases,visual maladies,neurodegenerative conditions,and a few X-linked ***/Cas9 system has been used to treat cancers through a variety of approaches,with sta-ble gene editing ***,the applications and clinical trials of CRisPR/Cas9 in various illnesses are *** to its high precision and efficiency,CRISPR/Cas9 strategies may treat gene-related illnesses by deleting,inserting,modifying,or blocking the expression of specific *** most challenging barrier to the in vivo use of CRISPR/Cas9 like off-target effects will be *** use of transfection vehicles for CRISPR/Cas9,including viral vectors(such as an Adeno-associated virus(AAV),and the development of non-viral vectors is also considered.

关键词： Clinical trials CRISPR/Cas9 Gene therapy Non-viral vectors Viral vectors

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PRC2 primes bivalent genes for transcription induction independent of histone methyltransferase activity

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Science China Life Sciences 2024年第9期67卷 2033-2035页

作者： Meihan Gong Ye Yuan Zhongye Dai Xuejiao Lv Jiacheng Su Dawei Huo Lin Niu Xu Chen Xudong Wu State Key Laboratory of Experimental Hematology The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) Department of Cell Biology School of Basic Medical Sciences Tianjin Medical University Bone Marrow Transplantation center the First Affiliated Hospital Zhejiang University School of Medicine Liangzhu Laboratory Institute of Hematology Zhejiang University

Dear Editor,Polycomb group proteins, conserved epigenetic transcriptional repressors, are crucial for orchestrating diverse developmental gene expression programs(Schuettengruber et al., 2017). The polycomb repressive complex 2(PRC2) catalyzes H3 lysine-27 trimethylation(H3K27me3) to establish a delicate balance with H3K4me3, forming a bivalent chromatin state at target gene promoters and thereby poising them for subsequent transcription activation(Bernstein et al.,2006).

关键词： REPRESSIVE COMPLEX 2 POLYCOMB PROMOTERS

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Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer:A systematic review

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World Journal of Gastrointestinal Oncology 2024年第1期16卷 197-213页

作者： Eman Al-Balushi Amina Al Marzouqi Shima Tavoosi Amir Hossein Baghsheikhi Arash Sadri Leyla Sharifi Aliabadi Mohammad-Mahdi Salarabedi Syed Azizur Rahman Nabeel Al-Yateem Alireza Mosavi Jarrahi Aram Halimi Mohammad Ahmadvand Wael M Abdel-Rahman College of Health Sciences University of SharjahSharjah 27272United Arab Emirates Department of biology Faculty of SciencesUniversity of IsfahanIsfahan 81746-73441Iran Department of biology Science and Research BranchIslamic Azad UniversityTehran 11365/4435Iran Students’Scientific Research center Tehran University of Medical SciencesTehran ***Iran cell Therapy and Hematopoietic Stem cell Transplantation Research center Research Institute for OncologyHematologyand Cell TherapyTehran University of Medical SciencesTehran ***Iran Student Research Committee School of MedicineShahid Beheshti University of Medical SciencesTehran ***Iran Department of Nursing University of SharjahSharjah 27272United Arab Emirates Cancer Research Centre Shahid Beheshti University of Medical SciencesTehran ***Iran Department of Medical Laboratory Sciences University of SharjahSharjah 27272United Arab Emirates

BACKGROUND Colorectal cancer(CRC)is the third most frequent and the second most fatal *** search for more effective drugs to treat this disease is ongoing.A better understanding of the mechanisms of CRC development and progression may reveal new therapeutic ***-specific peptidases(USPs),the largest group of the deubiquitinase protein family,have long been implicated in various *** have been numerous studies on the role of USPs in CRC;however,a comprehensive view of this role is *** To provide a systematic review of the studies investigating the roles and functions of USPs in *** We systematically queried the MEDLINE(via PubMed),Scopus,and Web of Science *** Our study highlights the pivotal role of various USPs in several processes implicated in CRC:Regulation of the cell cycle,apoptosis,cancer stemness,epithelial–mesenchymal transition,metastasis,DNA repair,and drug *** findings of this study suggest that USPs have great potential as drug targets and noninvasive biomarkers in *** dysregulation of USPs in CRC contributes to drug resistance through multiple *** Targeting specific USPs involved in drug resistance pathways could provide a novel therapeutic strategy for overcoming resistance to current treatment regimens in CRC.

关键词： Ubiquitin-specific peptidases Colorectal cancer Deubiquitinase protein family Drug target discovery Biomarker discovery

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Single-cell transcriptomic Atlas of aging macaque ocular outflow tissues

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Protein & cell 2024年第8期15卷 594-611页

作者： Jian Wu Chaoye Wang Shuhui Sun Tianmin Ren Lijie Pan Hongyi Liu Simeng Hou Shen Wu Xuejing Yan Jingxue Zhang Xiaofang Zhao Weihai Liu Sirui Zhu Shuwen Wei Chi Zhang Xu Jia Qi Zhang Ziyu Yu Yehong Zhuo Qi Zhao Chenlong Yang Ningli Wang Beijing Institute of Ophthalmology Beijing Tongren Eye CenterBeijing Tongren HospitalCapital Medical UniversityBeijing Key Laboratory of Ophthalmology and Visual SciencesBeijing 100730China State Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangzhou 510060China State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510060China State Key Laboratory of Membrane biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Beijing Institute for Stem cell and Regenerative Medicine Beijing 100101China Institute for Stem cell and Regeneration Chinese Academy of SciencesBeijing 100101China Department of Neurosurgery Peking University Third HospitalCenter for Precision Neurosurgery and Oncology of Peking University Health Science CenterBeijing 100191China Spencer center for Vision Research Byers Eye InstituteSchool of MedicineStanford UniversityPalo AltoCA 94304USA

The progressive degradation in the trabecular meshwork(TM)is related to age-related ocular diseases like primary open-angle ***,the molecular basis and biological significance of the aging process in TM have not been fully ***,we established a dynamic single-cell transcriptomic landscape of aged macaque TM,wherein we classified the outflow tissue into 12 cell subtypes and identified mitochondrial dysfunction as a prominent feature of TM ***,we divided TM cells into 13 clusters and performed an in-depth analysis on cluster O,which had the highest aging score and the most significant changes in cell proportions between the two ***,we found that the APOE gene was an important differentially expressed gene in cluster O during the aging process,highlighting the close relationship between cell migration and extracellular matrix regulation,and TM *** work further demonstrated that silencing the APOE gene could increase migration and reduce apoptosis by releasing the inhibition on the PI3K-AKT pathway and downregulating the expression of extracellular matrix components,thereby increasing the aqueous outflow rate and maintaining intraocular pressure within the normal *** work provides valuable insights for future clinical diagnosis and treatment of glaucoma.

关键词： single-cell transcriptomic atlas macaque trabecular meshwork ocular outflow tissue aging

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Stay in touch with the endoplasmic reticulum

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Science China(Life Sciences) 2024年第2期67卷 230-257页

作者： Sha Sun Gan Zhao Mingkang Jia Qing Jiang Shulin Li Haibin Wang Wenjing Li Yunyun Wang Xin Bian Yan G.Zhao Xun Huang Ge Yang Huaqing Cai Jose C.Pastor-Pareja Liang Ge Chuanmao Zhang Junjie Hu National Laboratory of Biomacromolecules Institute of BiophysicsUniversity of Chinese Academy of SciencesChinese Academy of SciencesBeijing 100101China The Ministry of Education Key Laboratory of cell Proliferation and Differentiation College of Life SciencesPeking UniversityBeijing 100871China State Key Laboratory of Membrane biology Tsinghua-Peking Center for Life SciencesSchool of Life SciencesTsinghua UniversityBeijing 100084China Laboratory of Computational biology&Machine Intelligence School of Artificial IntelligenceUniversity of Chinese Academy of SciencesBeijing 100049China State Key Laboratory of Medicinal Chemical biology College of Life SciencesNankai UniversityTianjin 300071China Brain Research center Department of BiologySchool of Life SciencesSouthern University of Science and TechnologyShenzhen 518055China State Key Laboratory of Molecular Developmental biology Institute of Genetics and Developmental BiologyInnovation Academy for Seed DesignChinese Academy of SciencesBeijing 100101China Institute of Neurosciences Consejo Superior de Investigaciones Científicas-Universidad Miguel HernándezSan Juan de Alicante 03550Spain

The endoplasmic reticulum(ER),which is composed of a continuous network of tubules and sheets,forms the most widely distributed membrane system in eukaryotic *** a result,it engages a variety of organelles by establishing membrane contact sites(MCSs).These contacts regulate organelle positioning and remodeling,including fusion and fission,facilitate precise lipid exchange,and couple vital signaling ***,we systematically review recent advances and converging themes on ER-involved organellar *** molecular basis,cellular influence,and potential physiological functions for ER/nuclear envelope contacts with mitochondria,Golgi,endosomes,lysosomes,lipid droplets,autophagosomes,and plasma membrane are summarized.

关键词： endoplasmic reticulum nuclear envelope mitochondria Golgi apparatus endosome lysosome lipid droplets autophagosome plasma membrane membrane contact site

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Id2 epigenetically controls CD8^(+)T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex

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cellular & Molecular Immunology 2024年第3期21卷 292-308页

作者： Yiming Li Mingwei Han Haolin Wei Wan Huang Zhinan Chen Tianjiao Zhang Meirui Qian Lin Jing Gang Nan Xiuxuan Sun Shuhui Dai Kun Wang Jianli Jiang Ping Zhu Liang Chen Department of cell biology of National Translational Science center for Molecular Medicine and Department of Clinical Immunology of Xijing Hospital Fourth Military Medical UniversityXi’anShaanxi 710032China State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases GanzhouJiangxi341000Xi’anShaanxi 710032China School of Medicine Shanghai UniversityShanghai 200444China

CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))*** of DNA binding protein 2(Id2)has been shown to play important roles in T-cell development and CD8^(+)T-cell ***,the role of Id2 in CD8^(+)T-cell exhaustion is ***,we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm *** deletion of Id2 dampens CD8^(+)T-cell-mediated immune responses and the maintenance of stem-like CD8^(+)T-cell subpopulations,suppresses PD-1 blockade and increases tumor ***,through its HLH domain,Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase ***,Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+Texprog *** LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing *** of LSD1 increases the abundance of Slamf6^(+)Tim-3^(−)Tex^(prog) cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+T *** study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)T-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

关键词： Id2 T-cell exhaustion Epigenetic modification Immune evasion

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Degeneration Directory:a multi-omics web resource for degenerative diseases

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Protein & cell 2024年第5期15卷 385-392页

作者： Haoteng Yan Changfa Lu Chenyang Lan Si Wang Weiqi Zhang Zan He Jinghao Hu Jiaqi Ai Guang-Hui Liu Shuai Ma Yuanchun Zhou Jing Qu State Key Laboratory of Membrane biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China State Key Laboratory of Stem cell and Reproductive biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Key Laboratory of Organ Regeneration and Reconstruction Institute of ZoologyChinese Academy of SciencesBeijing 100101China Advanced Innovation center for Human Brain Protection and National Clinical Research Center for Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China Aging Translational Medicine center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China Computer Network Information center Chinese Academy of SciencesBeijing 100190China The Fifth People’s Hospital of Chongqing Chongqing 400062China Aging Biomarker Consortium Beijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Sino-Danish College University of Chinese Academy of SciencesBeijing 101408China Beijing Institute for Stem cell and Regenerative Medicine Beijing 100101China Institute for Stem cell and Regeneration Chinese Academy of SciencesBeijing 100101China

Background of *** degeneration refers to the gradual decline in organ function and structure deterioration that occurs during aging,which represents the greatest risk factor for various degenerative diseases,including cardiovascular diseases,neurodegenerative diseases,and osteoarthritis,etc.(Aging Biomarker et al.,2023;Becker et al.,2018;Cai et al.,2022).

关键词： Directory web Becker

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Impairment of Autophagic Flux After Hypobaric Hypoxia Potentiates Oxidative Stress and Cognitive Function Disturbances in Mice

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Neuroscience Bulletin 2024年第1期40卷 35-49页

作者： Shuhui Dai Yuan Feng Chuanhao Lu Hongchen Zhang Wenke Ma Wenyu Xie Xiuquan Wu Peng Luo Lei Zhang Fei Fei Zhou Fei Xia Li Department of Neurosurgery Xijing HospitalFourth Military Medical UniversityXi'an 710000China National Translational Science center for Molecular Medicine and Department of cell biology Fourth Military Medical UniversityXi'an 710000China Department of Neurosurgery The Central Hospital of BaojiBaoji 721000China Department of Ophthalmology Xijing HospitalFourth Military Medical UniversityXi'an 710000China

Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude *** plays a critical role in ischemic brain injury,but its role in hypo-baric hypoxia(HH)remains *** we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain,and is partially responsible for HH-induced oxidative stress,neuronal loss,and brain *** autophagic agonist rapamycin only promotes the initiation of *** proteome analysis,a screen showed that protein dynamin2(DNM2)potentially regulates autophagic *** of DNM2 significantly increased the formation of autolysosomes,thus maintaining autophagic flux in combination with ***,the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH *** results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.

关键词： Autophagy-Proteomics Oxidative stress Hypobaric hypoxia-Brain injury

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T cell receptor signaling and cell immunotherapy

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National Science Open 2024年第4期3卷 156-171页

作者： Linsong Zhang Xinyi Xu Xiaoshan Shi Chenqi Xu Key Laboratory of Quantitative Synthetic biology Shenzhen Institute of Synthetic BiologyShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China State Key Laboratory of Molecular biology CAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China

As the major sensor of adaptive immune system,T cell receptor(TCR)can recognize diverse antigens and initiate specific immune responses against invading pathogens and cancer *** the mechanisms of TCR signaling has led to the development of engineered T cell therapies,which have extensive applications in the treatment of diseases such as cancer,infection and ***,we review the current understanding of antigen-induced TCR signaling and discuss its applications in T cell therapies.

关键词： T cell receptor-CD3 complex signaling T cell therapy

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PCAF-mediated acetylation of METTL3 impairs mRNA translation efficiency in response to oxidative stress

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Science China Life Sciences 2024年第10期67卷 2157-2168页

作者： Cheng Liu Miao Yu Mengyuan Wang Siyuan Yang Yenan Fu Lei Zhang Chaoyang Zhu Hongquan Zhang Program for Cancer and cell biology Department of Human AnatomyHistology and EmbryologySchool of Basic Medical SciencesPeking University International Cancer Instituteand State Key Laboratory of Molecular OncologyPeking University Health Science Center Department of General Surgery and Urological Surgery Huaihe HospitalHenan University Department of Human Anatomy Histologyand EmbryologyShenzhen University School of Medicine

METTL3 methylates RNA and regulates the fate of mRNA through its methyltransferase activity. METTL3 enhances RNA translation independently of its catalytic activity. However, the underlying mechanism is still elusive. Here, we report that METTL3 is both interacted with and acetylated at lysine 177 by the acetyltransferase PCAF and deacetylated by SIRT3. Neither the methyltransferase activity nor the stability of METTL3 is affected by its acetylation at K177. Importantly, acetylation of METTL3 blocks its interaction with EIF3H, a subunit of the translation initiation factor, thereby reducing mRNA translation efficiency. Interestingly, acetylation of METTL3 responds to oxidative stress. Mechanistically, oxidative stress enhances the interaction of PCAF with METTL3, increases METTL3 acetylation, and suppresses the interaction of METTL3 with EIF3H, thereby decreasing the translation efficiency of ribosomes and inhibiting cell proliferation. Altogether,we suggest a mechanism by which oxidative stress regulates RNA translation efficiency by the modulation of METTL3 acetylation mediated by PCAF.

关键词： METTL3 acetylation PCAF m6A oxidative stress translation SIRT3

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