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Human 8-cell embryos enable efficient induction of disease-preventive mutations without off-target effect by cytosine base editor

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Protein & Cell 2023年第6期14卷 416-432页

作者： Yinghui Wei Meiling Zhang Jing Hu yingsi zhou Mingxing Xue Jianhang Yin Yuanhua Liu Hu Feng Ling zhou Zhifang Li Dongshuang Wang Zhiguo Zhang Yin zhou Hongbin Liu Ning Yao Erwei Zuo Jiazhi Hu Yanzhi Du Wen Li Chunlong Xu Hui Yang Center for Reproductive Medicine International Peace Maternity and Child Health HospitalInnovative Research Team of High-level Local Universities in ShanghaiSchool of MedicineShanghai Jiao Tong UniversityShanghai 2000301.Center for Reproductive MedicineInternational Peace Maternity and Child Health HospitalInnovative Research Team of High-level Local Universities in ShanghaiSchool of MedicineShanghai Jiao Tong UniversityShanghai 200030China Institute of Neuroscience State Key Laboratory of NeuroscienceKey Laboratory of Primate NeurobiologyCAS Center for Excellence in Brain Science and Intelligence TechnologyShanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai 200031China Lingang Laboratory Shanghai Research Center for Brain Science and Brain-Inspired Intelligence TechnologyShanghai 200031China Center for Reproductive Medicine Ren Ji HospitalSchool of MedicineShanghai Key Laboratory for Assisted Reproduction and Reproductive GeneticsShanghai Jiao Tong UniversityShanghai 200127China The MOE Key Laboratory of Cell Proliferation and Differentiation School of Life SciencesGenome Editing Research CenterPeking UniversityBeijing 100871China Center for Reproductive Medicine Shandong UniversityJinan 250012China Center for Reproductive Medicine Anhui Provincial Maternal and Child Health HospitalHefei 230001China Shenzhen Branch Guangdong Laboratory for Lingnan Modern AgricultureGenome Analysis Laboratory of the Ministry of AgricultureAgricultural Genomics Institute at ShenzhenChinese Academy of Agricultural SciencesShenzhen 518000China Reproductive Medicine Center Department of Obstetrics and Gynecologythe First Affiliated Hospital of Anhui Medical UniversityHefei 230022China

Approximately 140 million people worldwide are homozygous carriers of APOE4(ε4),a strong genetic risk factor for late onset familial and sporadic Alzheimer’s disease(AD),91%of whom will develop AD at earlier age than heterozygous carriers and noncarriers.Susceptibility to AD could be reduced by targeted editing of APOE4,but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies.Here,we first screened eight cytosine base editor variants at four injection stages(from 1-to 8-cell stage),and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate(up to 100%)with the lowest bystander effects.In particular,80%of AD-susceptibleε4 allele copies were converted to the AD-neutralε3 allele in humanε4-carrying embryos.Stringent control measures combined with targeted deep sequencing,whole genome sequencing,and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells.Furthermore,base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage.Finally,we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia.Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos,a potential approach for reducing human susceptibility to AD or other genetic diseases.

关键词： human embryo APOE4 disease-preventive mutations base editor

An engineered xCas12i with high activity,high specificity,and broad PAM range

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Protein & Cell 2023年第7期14卷 540-545页

作者： Hainan Zhang Xiangfeng Kong Mingxing Xue Jing Hu Zikang Wang Yinghui Wei Haoqiang Wang Jingxing zhou Weihong Zhang Mengqiu Xu Xiaowen Shen Fengcai Yin Zhiyuan Ai Guangyan Huang Junhui Xia Xueqiong Song Hengbin Li Yuan Yuan Jinhui Li Na Zhong Meiling Zhang yingsi zhou Hui Yang HuiEdit Therapeutics Co. Ltd.Shanghai 200120China HuiGene Therapeutics Co. Ltd.Shanghai 200120China Center for Reproductive Medicine International Peace Maternity and Child Health HospitalInnovative Research Team of High-level Local Universities in ShanghaiSchool of MedicineShanghai Jiao Tong UniversityShanghai 200030China

Dear Editor,The clustered regularly interspaced short palindromic repeats-Cas(CRISPR-Cas)systems,including type II Cas9 and type V Cas12 systems,which serve in the adaptive immunity of prokaryotes against viruses,have been developed into genome-editing tools(Anzalone et al.,2020;Doudna,2020).Compared with type II systems,the type V systems including V-A to V-K showed more functional diversity(Yan et al.,2019).Amongst them,Cas12i has a relatively smaller size(1,033-1,093 aa),compared to SpCas9 and Cas12a,and has a 5'-TTN protospacer adjacent motif(PAM)preference(Yan et al.,2019).

关键词： high specificity

CasRx-mediated RNA targeting prevents choroidal neovascularization in a mouse model of age-related macular degeneration

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National Science Review 2020年第5期7卷 835-837页

作者： Changyang zhou Xinde Hu Cheng Tang Wenjia Liu Shaoran Wang yingsi zhou Qimeng Zhao Qiyu Bo Linyu Shi Xiaodong Sun Haibo zhou Hui Yang Institute of Neuroscience State Key Laboratory of Neuroscience Key Laboratory of Primate Neurobiology CAS Center for Excellence in Brain Science and Intelligence Technology Shanghai Research Center for Brain Science and Brain-Inspired Intelligence Shanghai Institutes for Biological Sciences Chinese Academy of Sciences College of Life Sciences University of Chinese Academy of Sciences Department of Ophthalmology Shanghai General Hospital (Shanghai First People’s Hospital)Shanghai Jiao Tong University School of MedicineShanghai Key Laboratory of Fundus Diseases

RNA-targeting CRISPR system Cas13 offers an efficient approach for manipulating RNA transcripts in vitro. In this perspective, we provide a proof-of-concept demonstration that Cas13-mediated Vegfa knockdown in vivo co... 详细信息

关键词： AAV AMD RNA CasRx-mediated RNA targeting prevents choroidal neovascularization in a mouse model of age-related macular degeneration

Precise genome editing without exogenous donor DNA via retron editing system in human cells

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Protein & Cell 2021年第11期12卷 899-902页

作者： Xiangfeng Kong Zikang Wang Renxia Zhang Xing Wang yingsi zhou Linyu Shi Hui Yang HUIGENE Therapeutics Inc. Shanghai 200131China Institute of Neuroscience State Key Laboratory of NeuroscienceKey Laboratory of Primate NeurobiologyCenter for Excellence in Brain Science and Intelligence TechnologyChinese Academy of SciencesShanghai 200031China College of Life Sciences University of Chinese Academy of SciencesBeijing 100049China Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology Shanghai 201210China

Dear Editor,CRISPR-Cas9 mediated seamless genome editing can be achieved by incorporating donor DNA into the CRISPR-Cas9 target loci via homology-directed repair(HDR),albeit with relative low efficiency due to the inefficient delivery of exogenous DNA(Cox et al.,2015;Gao,2021).Retrons are bacterial phage-defense related operons composed of a specialized reverse transcriptase(RT)and a relevant non-coding RNA(ncRNA)which can be partially reverse tran-scribed by RT initiating at a conserved guanosine(G)residue to produce a multicopy single-stranded DNA(msDNA)(Yee et al.,1984;Millman et al.,2020).After being reverse transcribed,the msDNA is usually covalently teth-ered to the ncRNA through the 2',5'-phosphodiesterbond between the priming G in ncRNA and 5'end of msDNA(Dhundale et al.,1987).The reverse transcription process,of which the specialized RT recognizes the unique secondary structure of retron ncRNA,is highly specific(Hsu et al.,1989).Additionally,desired msDNA can be generated in vivo by replacing the dispensable region of retron ncRNA with desired sequences(Mirochnitchenko et al.,1994;Simon et al.,2019).Therefore,retrons are promising biological sources for in vivo generation of DNA donors for HDR-me-diated precise genome editing.

关键词： donor specialized editing

Indiscriminate ssDNA cleavage activity of CRISPR-Cas12a induces no detectable off-target effects in mouse embryos

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Protein & Cell 2021年第9期12卷 741-745页

作者： Yu Wei yingsi zhou Yajing Liu Wenqin Ying Ruiming Lv Qimeng Zhao Haibo zhou Erwei Zuo Yidi Sun Hui Yang Changyang zhou Institute of Neuroscienee State Key Laboratory of NeuroscieneeKey Laboratory of Primate NeurobiologyCenter for Excellence in Brain Science and Intelligenee TechnologyChinese Academy of SciencesShanghai 200031China University of Chinese Academy of Sciences Beijing 100049China Shanghai Center for Brain Science and Brairvlnspired Intelligence Technology Shanghai 201210China Center for Animal Genomics Agricultural Genome Institute at ShenzhenChinese Academy of Agricultural SciencesShenzhen 518124China

Dear Editor,Newly discovered characteristics like"collateral effect"or trans-cleavage in CRISPR-Cas13 and CRISPR-Cas12 systems have enabled their usage in nucleic acid detection(Gootenberg et al.2017,2018;Chen et al.2018).The collateral RNA cleavage of Cas13a has been reported to be harmful for cell development(Wang et al.2019;Buchman et al.2020).As a representative gene editor of CRISPR-Cas12 system,CRISPR-Cas12a(Cpf1)holds great potential for therapeutic applications in the future(Zetsche et al.2015;Koo et al.2018;Campa et al.2019).

关键词： al. cleavage holds

Modulation of metabolic functions through Cas13d-mediated gene knockdown in liver

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Protein & Cell 2020年第7期11卷 518-524页

作者： Bingbing He Wenbo Peng Jia Huang Hang Zhang yingsi zhou Xiali Yang Jing Liu Zhijle Li Chunlong Xu Mingxing Xue Hui Yang Pengyu Huang Instute of Neuroscience State Key Laboratory of NeuroscienceKey Laboratory of Primate NeurobiologyCAS Center for Excellence in Brain Science and Itelligence Technology.Shanghai Research Center for Brain Science and Brain-Inspired ItelligenceShanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai 200031China School of Life Science and Technology.ShanghaiTech University Shanghai 201210China College of Life Sciences University of Chinese Academy of SciencesBeljing 100049China Center for Animal Genomics Agricultural Genome Institute at ShenzhenChinese Academy of Agricultural SciencesShenzhen 518124China CAS Center for Excellence in Molecular Cell Science Chinese Academy ot ScencesShanghal 200031China

Dear Editor,RNA knockdown in vivo carries significant potential for dis-ease modeling and therapies.Despite the emerging approaches of CRISPR/Cas9-mediated permanent knock out of targeted genes,strategies targeting RNA for disruption are advantageous in the treatment of acquired metabolic disorders when permanent modification of genome DNA is not appropriate,and RNA virus infection diseases when pathogenic DNA is not available(such as SARS-Cov-2 and MERS infections).

关键词： CRISPR/Cas9 mediated diseases

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强化语言知识:英语课程培养核心素养的关键

教育学术月刊 2024年第2期 65-72页

作者：王卉黄颖思北京师范大学教育学部北京100875 厦门工学院外国语学院福建厦门361021

语言能力、文化意识、思维品质、学习能力等核心素养的提出,体现了英语课程从重视外在的“知识的意义”到重视内部的“人的价值”的转变,具有重大的理论意义。然而,核心素养的落地不能仅仅依靠“活动“”交流“”分析“”思维导图”等策... 详细信息

语言能力、文化意识、思维品质、学习能力等核心素养的提出,体现了英语课程从重视外在的“知识的意义”到重视内部的“人的价值”的转变,具有重大的理论意义。然而,核心素养的落地不能仅仅依靠“活动“”交流“”分析“”思维导图”等策略,且这些策略的有效推行也离不开扎实的语言知识这一基础。无论是从语言学还是教学论的角度来看,语言知识都是核心素养的关键。因此,要培养学生的核心素养,就需要科学、合理地抓好语言知识的教学。

关键词：语言知识学生核心素养策略

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素养如何落地生根:回归语言知识的意义

外国语文 2024年第2期40卷 186-196页

作者：王卉黄颖思厦门工学院外国语学院福建厦门361021 北京师范大学教育学部北京100875

已有关于英语核心素养的研究并不强调语言知识的重要性。无论是学术研究还是一线实践,语言知识均处于一种被“放逐”的状态。然而,语言学、教学论的经典理论均表明,语言知识是核心素养的重要成分,也是素养发展的前提和基础。因此,英语... 详细信息

已有关于英语核心素养的研究并不强调语言知识的重要性。无论是学术研究还是一线实践,语言知识均处于一种被“放逐”的状态。然而,语言学、教学论的经典理论均表明,语言知识是核心素养的重要成分,也是素养发展的前提和基础。因此,英语课程要培养核心素养,就需要回归语言知识。一方面,可以通过设计基于“两次倒转”理论的教学路径,来促进“习得”与“学得”路线的相互融合;另一方面,应推动英语课程内容的结构化,实现语言“意义”与语言“形式”的有机统一。

关键词：语言知识核心素养习得学得

法国公共图书馆参与数字文化遗产项目开发研究与启示

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图书馆 2024年第5期 49-56页

作者：徐彤阳黄映思山西财经大学信息学院太原030006

文章梳理法国公共图书馆数字文化遗产的相关战略计划,探析其驱动因素。以4所具有代表性的公共图书馆作为研究主体,对法国图书馆的数字文化遗产项目实践情况进行分析,并提出对我国公共图书馆参与数字文化遗产保护战略的有益启示。

关键词：法国公共图书馆文化遗产数字人文

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