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Drosophila models used to simulate human ATP1A1 gene mutations that cause Charcot-Marie-Tooth type 2 disease and refractory seizures

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Neural Regeneration Research 2025年第1期20卷 265-276页

作者： Yao Yuan Lingqi Yu Xudong Zhuang Dongjing Wen Jin He Jingmei Hong Jiayu Xie Shengan Ling Xiaoyue Du Wenfeng Chen Xinrui Wang Institute of Life Sciences College of Biological Science and EngineeringFuzhou UniversityFuzhouFujian ProvinceChina NHC key laboratory of Technical Evaluation of Fertility regulation for Non-human Primate(Fujian Maternity and Child Health Hospital) FuzhouFujian ProvinceChina Medical Research Center Fujian Maternity and Child Health HospitalCollege of Clinical Medicine for Obstetrics&Gynecology and PediatricsFujian Medical UniversityFuzhouFujian ProvinceChina Department of Neurology and Institute of Neurology of The First Affiliated Hospital Institute of Neuroscienceand Fujian Key Laboratory of Molecular NeurologyFujian Medical UniversityFuzhouFujian ProvinceChina

Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory *** develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause *** located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)*** addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive *** these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut *** found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in *** heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal *** Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.

关键词： ATP1A1 Atpα bang-sensitive paralysis Charcot-Marie-Tooth disease type 2 CRISPR/Cas9 homology-directed repair Na^(+)/K^(+)-ATPase point mutation seizures sodium pump

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Production of non-mosaic genome edited porcine embryos by injection of CRISPR/Cas9 into germinal vesicle oocytes

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Journal of genetics and Genomics 2019年第7期46卷 335-342页

作者： Xiaohu Su Wei Chen Qingqing Cai Puping Liang Yaosheng Chen Peiqing Cong Junjiu Huang key laboratory of Reproductive Medicine of Guangdong Province First Affiliated Hospital and School of Life Sciences Sun Yat-sen University Guangzhou 510275 China moe key laboratory of gene function and regulation State Key Laboratory of Biocontrol School of Life Sciences Sun Yat-sen University Guangzhou 510275 China key laboratory of Reproductive Medicine of Guangdong Province Third Affiliated Hospital of Guangzhou Medical University Guangzhou 510150 China

genetically modified pigs represent a great promise for generating models of human diseases and producing new *** of genetically edited pigs using somatic cell nuclear transfer(SCNT)or zygote cytoplasmic microinjection is a tedious process due to the low developmental rate or mosaicism of the founder(FO).Herein,we developed a method termed germinal vesicle oocyte gene editing(GVGE)to produce non-mosaic porcine embryos by editing maternal alleles during the GV to MII *** of Cas9 mRNA and X-linked Dmd gene-specific gRNA into GV oocytes did not affect their developmental *** MII oocytes edited during in vitro maturation(IVM)could develop into blastocysts after parthenogenetic activation(PA)or in vitro fertilization(IVF).Genotyping results indicated that the maternal gene X-linked Dmd could be efficiently edited during oocyte *** to81.3% of the edited IVF embryos were non-mosaic Dmd gene mutant *** conclusion,GVGE might be a valuable method for the generation of non-mosaic maternal allele edited FO embryos in a short simple step.

关键词： Porcine Germinal vesicle(GV) In vitro maturation CRISPR/Cas9 Dmd

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Effective generation of maternal genome point mutated porcine embryos by injection of cytosine base editor into germinal vesicle oocytes

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Science China(Life Sciences) 2020年第7期63卷 996-1005页

作者： Xiaohu Su Wei Chen Qingqing Cai Puping Liang Yaosheng Chen Peiqing Cong Junjiu Huang key laboratory'of Reproductive Medicine of Guangdong Province the First Affiliated Hospital and School of Life SciencesSun Yat-sen UniversityGuangzhou 510275China moe key laboratory of gene function and regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China key laboratory of Reproductive Medicine of Guangdong Province the Third Affiliated Hospital of Guangzhou Medical University'Guangzhou 510150China

Cytosine and adenine base editors are promising new tools for introducing precise genetic modifications that are required to generate disease models and to improve traits in pigs. Base editors can catalyze the conversion of C→T(C>T) or A→G(A>G) in the target site through a single guide RNA. Injection of base editors into the zygote cytoplasm can result in the production of offspring with precise point mutations, but most F0 are mosaic, and breeding of F1 heterozygous pigs is time-intensive. Here, we developed a method called germinal vesicle oocyte base editing(GVBE) to produce point mutant F0 porcine embryos by editing the maternal alleles during the GV to MⅡ transition. Injection of cytosine base editor 3(BE3) mRNA and X-linked Dmdspecific guide RNAs into GVoocytes efficiently edited maternal Dmd during in vitro maturation and did not affect the maturation potential of the oocytes. The edited MⅡ oocytes developed into blastocysts after parthenogenetic activation(PA) or in vitro fertilization(IVF). However, BE3 may reduce the developmental potential of IVF blastocysts from 31.5%±0.8% to 20.4%±2.1%. There 40%–78.3% diploid PA blastocysts had no more than two different alleles, including up to 10% embryos that had only C>T mutation alleles. Genotyping of IVF blastocysts indicated that over 70% of the edited embryos had one allele or two different alleles of Dmd. Since the male embryos had only a copy of Dmd allele, all five(5/19) F0 male embryos are homozygous and three of them were Dmd precise C>T mutation. Nine(9/19) female IVF embryos had two different alleles including a WT and a C>T mutation. DNA sequencing showed that some of them might be heterozygous embryos. In conclusion, the GVBE method is a valuable method for generating F0 embryos with maternal point mutated alleles in a single step.

关键词： cytosine base editor point mutation porcine germinal vesicle oocyte maternal genome Dmd

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ILF3 safeguards telomeres from aberrant homologous recombination as a telomeric R-loop reader

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Protein & Cell 2024年第7期15卷 493-511页

作者： Chuanle Wang Yan Huang Yue Yang Ruofei Li Yingying Li Hongxin Qiu Jiali Wu Guang Shi Wenbin Ma Zhou Songyang moe key laboratory of gene function and regulation State Key Laboratory of Biocontrol and Guangzhou Key Laboratory of Healthy AgingSchool of LifesciencesSun Yat-sen UniversityGuangzhou 510275China Department of Oncology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510275China Department of Nephrology The First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China

Telomeres are specialized structures at the ends of linear chromosomes that protect genome *** telomeric repeat-containing RNA(TERRA)that is transcribed from subtelomeric regions can invade into double-stranded DNA regions and form RNA:DNA hybrid-containing structure called *** tumor cells,R-loop formation is closely linked to gene expression and the alternative lengthening of telomeres(ALT)*** R-loops can cause stalled replication forks and telomere ***,how R-loops are recognized and regulated,particularly at telomeres,is not well *** discovered that ILF3 selectively associates with telomeric R-loops and safeguards telomeres from abnormal homologous *** out ILF3 results in excessive R-loops at telomeres and triggers telomeric DNA damage *** addition,ILF3 deficiency disrupts telomere homeostasis and causes abnormalities in the ALT *** the proximity-dependent biotin identification(BioID)technology,we mapped the ILF3 interactome and discovered that ILF3 could interact with several DNA/RNA helicases,including ***,ILF3 may aid in the resolution of telomeric R-loops through its interaction with *** findings suggest that ILF3 may function as a reader of telomeric R-loops,helping to prevent abnormal homologous recombination and maintain telomere homeostasis.

关键词： ILF3 RNA:DNA hybrids telomeric R-loops homologous recombination telomeric DNA damage responses

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cGAS guards against chromosome endto-end fusions during mitosis and facilitates replicative senescence

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Protein & Cell 2022年第1期13卷 47-64页

作者： Xiaocui Li Xiaojuan Li Chen Xie Sihui Cai Mengqiu Li Heping Jin Shu Wu Jun Cui Haiying Liu Yong Zhao moe key laboratory of gene function and regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yatsen UniversityGuangzhou 510006China State key laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510006China Department of Biochemistry School of Life SciencesSun Yat-sen UniversityGuangzhou 510006China

As a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.

关键词： cGAS telomeres chromosome end-toend fusion DNA damage response non-homologous end joining mitosis genome stability

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RNA-induced liquid phase separation of SARS-CoV-2 nucleocapsid protein facilitates NF-kB hyper-activation and inflammation

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Signal Transduction and Targeted Therapy 2021年第5期6卷 1601-1613页

作者： Yaoxing Wu Ling Ma Sihui Cai Zhen Zhuang Zhiyao Zhaou Shouheng Jin Weihong Xie Lingli Zhou Lei Zhang Jincun Zhao Jun Cui moe key laboratory of gene Funrtion and regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen UniversityGuangzhouGuangdongChina State key laboratory of Respiratory Disease Guangzhou Institute of Respiratory DiseaseThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina

The ongoing 2019 novel coronavirus disease(COVID-19)caused by SARS-CoV-2 has posed a worldwide pandemic and a major global public health *** severity and mortality of COVID-19 are associated with virus-induced dysfunctional inflammatory responses and cytokine ***,the interplay between host inflammatory responses and SARS-CoV-2 infection remains largely ***,we demonstrate that SARS-CoV-2 nucleocapsid(N)protein,the major structural protein of the virion,promotes the virus-triggered activation of NF-kB *** binding to viral RNA,N protein robustly undergoes liquid-liquid phase separation(LLPS),which recruits TAK1 and IKK complex,the key kinases of NF-kB signaling,to enhance NF-kB ***,1,6-hexanediol,the inhibitor of LLPS,can attenuate the phase separation of N protein and restrict its regulatory functions in NF-kB *** results suggest that LLPS of N protein provides a platform to Induce NF-kB hyper-activation,which could be a potential therapeutic target against COVID-19 severe pneumonia.

关键词： inflammation separation activation

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The functional analysis of transiently upregulated miR-101 suggests a “braking” regulatory mechanism during myogenesis

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Science China(Life Sciences) 2021年第10期64卷 1612-1623页

作者： Shurong Liu Shujuan Xie Huafeng Chen Bin Li Zhirong Chen Yeya Tan Jianhua Yang Lingling Zheng Zhendong Xiao Qi Zhang Lianghu Qu moe key laboratory of gene function and regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China Vaccine Research Institute of Sun Yat-sen University the Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510630China Cell-gene Therapy Translational Medicine Research Center the Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510630China

Skeletal muscle differentiation is a highly coordinated process that involves many cellular signaling pathways and microRNAs(miRNAs).A group of muscle-specific miRNAs has been reported to promote myogenesis by suppressing key signaling pathways for cell ***,the functional role and regulatory mechanism of most non-muscle-specific miRNAs with stage-specific changes during differentiation are largely ***,we describe the functional characterization of miR-101a/b,a pair of non-muscle-specific miRNAs that show the largest change among a group of transiently upregulated miRNAs during myogenesis in C2C12 *** overexpression of miR-101a/b inhibits myoblast differentiation by suppressing the p38/MAPK,Interferon Gamma,and Wnt pathways and enhancing the C/EBP ***2a,a key protein in the p38/MAPK pathway,was identified as a direct target of miR-101a/***,we found that the long non-coding RNA(lncRNA)Malat1,which promotes muscle differentiation,interacts with miR-101a/b,and this interaction competes with Mef2a mRNA to relieve the inhibition of the p38/MAPK pathway during *** results uncovered a“braking”role in differentiation of transiently upregulated miRNAs and provided new insights into the competing endogenous RNA(ceRNA)regulatory mechanism in myoblast differentiation and myogenesis.

关键词： miR-101a/b p38/MAPK signaling pathway Mef2a Malat1 skeletal muscle differentiation

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Noncoding RNA:from dark matter to bright star

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Science China(Life Sciences) 2020年第4期63卷 463-468页

作者： Yuanchao Xue Runsheng Chen Lianghu Qu Xiaofeng Cao key laboratory of RNA Biology Institute of BiophysicsChinese Academy of SciencesBeijing 100101China moe key laboratory of gene function and regulation State Key Laboratory for BiocontrolSchool of Life SciencesSun Yat-Sen UniversityGuangzhou 510275China State key laboratory of Plant Genomics and National Center for Plant gene Research(Beijing) Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China

The central dogma states that genes encoded in the DNA should be first transcribed into messenger RNA(mRNA)and then translated into functional proteins(Crick,1970).This dogma has been written in numerous textbooks and learned by myriad ***,along with the completion of the human genome project in June 2000,an astonishing fact was revealed:only 1.5%of the human genome encodes for proteins(Lander et al.,2001;Venter et al.,2001).This fact raised three fundamental questions:(i)why does the human genome have so few protein-coding genes?(ii)how to explain the apparent differences between humans and other species using the limited coding genes?(iii)what are the roles of the noncoding regions in our genome?

关键词： al. apparent raised

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Correction of a CADASIL point mutation using adenine base editors in hiPsCsandbloodvessel organoids

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Journal of genetics and Genomics 2024年第2期51卷 197-207页

作者： Jingwen Wang Lei Zhang Guanglan Wu Jinni Wu Xinyao Zhou Xiaolin Chen Yongxia Niu Yiren Jiao Qianyi Liu Puping Liang Guang Shi Xueqing Wu Junjiu Huang moe key laboratory of gene function and regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen UniversityGuangzhouGuangdong 510275China key laboratory of Reproductive Medicine of Guangdong Province The First Affiliated Hospital and School of Life SciencesSun Yat-sen UniversityGuangzhouGuangdong 510275China Center of Reproductive Medicine Children's Hospital of Shanxi and Women Health Center of ShanxiTaiyuanShanxi 030013China

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small vessel disease caused by mutations in the NOTCH3 gene. However, the pathogenesis of CADASIL remains unclear, and patients have limited treatment options. Here, we use human induced pluripotent stem cells (hiPSCs) generated from the peripheral blood mononuclear cells of a patient with CADASIL carrying a heterozygous NOTCH3 mutation (c.1261C>T, p.R421C) to develop a disease model. The correction efficiency of different adenine base editors (ABEs) is tested using the HEK293T-NOTCH3 reporter cell line. ABEmax is selected based on its higher efficiency and minimization of predicted off-target effects. Vascular smooth muscle cells (VSMCs) differentiated from CADASIL hiPSCs show NOTCH3 deposition and abnormal actin cytoskeleton structure, and the abnormalities are recovered in corrected hiPSC-derived VSMCs. Furthermore, CADASIL blood vessel organoids generated for in vivo modeling show altered expression of genes related to disease phenotypes, including the downregulation of cell adhesion, extracellular matrix organization, and vessel development. The dual adeno-associated virus (AAV) split-ABEmax system is applied to the genome editing of vascular organoids with an average editing efficiency of 8.82%. Collectively, we present potential genetic therapeutic strategies for patients with CADASIL using blood vessel organoids and the dual AAV split-ABEmax system.

关键词： CADASIL Induced pluripotent stem cells Adenine base editors AAV Blood vessel Organoid

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Homology-based repair induced by CRISPR-Cas nucleases in mammalian embryo genome editing

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Protein & Cell 2022年第5期13卷 316-335页

作者： Xiya Zhang Tao Li Jianping Ou Junjiu Huang Puping Liang Center for Reproductive Medicine the Third Affiliated Hospital of Sun Yat-sen UniversitySun Yat-sen UniversityGuangzhou 510630China moe key laboratory of gene function and regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China key laboratory of Reproductive Medicine of Guangdong Province the First Affiliated Hospital and School of Life SciencesSun Yat-sen UniversityGuangzhou 510275China

Recent advances in genome editing,especially CRISPR-Cas nucleases,have revolutionized both laboratory research and clinical ***-Cas nucleases,together with the DNA damage repair pathway in cells,enable both genetic diversification by classical non-homologous end joining(c-NHEJ)and precise genome modification by homology-based repair(HBR).Genome editing in zygotes is a convenient way to edit the germline,paving the way for animal disease model generation,as well as human embryo genome editing therapy for some life-threatening and incurable *** efficiency is highly dependent on the DNA donor that is utilized as a repair ***,we review recent progress in improving CRISPR-Cas nuclease-induced HBR in mammalian embryos by designing a suitable DNA ***,we want to provide a guide for producing animal disease models and correcting genetic mutations through CRISPR-Cas nuclease-induced HBR in mammalian ***,we discuss recent developments in precise genome-modification technology based on the CRISPR-Cas system.

关键词： homology-based repair(HBR) genome editing disease modeling embryo precision medicine

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