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| 1 | CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes显示文摘染色体编辑工具例如定期聚类短 palindromic 重复(CRISPR ) 联系了的 interspaced 系统(Cas ) 广泛地被用来包括动物接合子和人的房间在模型系统修改基因,并且为基本研究和临床的应用保持巨大的诺言。迄今为止,严肃的知识差距在人的早胚胎,并且在效率和在人的培植前胚胎使用象 CRISPR/Cas9 那样的技术的潜在的离开目标效果留在我们 DNA 修理机制的理解。在这份报告,我们使用了推进的接合子调查 CRISPR/Cas9-mediated 基因在人的房间编辑的 tripronuclear (3PN ) 。我们发现 CRISPR/Cas9 能有效地劈开内长的 -globin 基因(HBB ) 。然而,相应再结合的效率指导了 HBB 的修理(HDR ) 是低的,编辑胚胎是马赛克。离开目标劈开在由 T7E1 试金并且 whole-exome 定序揭示了的这些 3PN 接合子也是明显的。而且,内长的 delta-globin 基因(HBD ) 对 HBB 相应,与外长的施主 oligos 竞争了充当修理模板,导致倔强的变化。我们的数据也显示在这些胚胎的 HBB 地点的修理通过非转线路 HDR 小径优先地发生了。一起拿,我们的工作加亮紧迫的需要进一步改进 CRISPR/Cas9 平台的忠实和特性,为编辑的 CRSIPR/Cas9-mediated 的任何临床的应用程序的一个前提。 | Puping Liang Yanwen Xu Xiya Zhang Chenhui Ding Rui Huang Zhen Zhang Jie Lv Xiaowei Xie Yuxi Chen Yujing Li Ying Sun Yaofu Bai Zhou Songyang Wenbin Ma Canquan Zhou Junjiu Huang | 2015 | Protein & Cell2015，6，5： | 149 |
| 2 | Correction of β-thalassemia mutant by base editor in human embryos显示文摘 | Puping Liang Chenhui Ding Hongwei Sun Xiaowei Xie Yanwen Xu Xiya Zhang Ying Sun Yuanyan Xiong Wenbin Ma Yongxiang Liu Yali Wang Jianpei Fang Dan Liu Zhou Songyang Canquan Zhou Junjiu Huang | 2017 | Protein & Cell2017，8，11： | 34 |
| 3 | Effective gene editing by high-fidelity base editor 2 in mouse zygotes显示文摘通过相应再结合的指向的点 mutagenesis 广泛地在基因研究被使用了并且为在病人修理引起疾病的变化保持可观的诺言。然而,象 mosaicism 那样的问题和低 mutagenesis 效率继续提出挑战到如此的途径的临床的申请。最近,一个基础编辑器() 在 cytidine (C) 脱氨基酶上造的系统和 CRISPR/Cas9 技术在植物,酵母,和人的房间为指向的点 mutagenesis 作为一个其他的方法被开发。然而,基础编辑器高效地在 deamination 窗口中把 C 变换成 thymidine (T) 是否指向了在鼠标胚胎的基础编辑,仍然保持不清楚是可行的。在这份报告,我们产生了基础编辑的一个修改高保真版本 2 (HF2-BE2 ) ,并且调查了它在老鼠胚胎编辑功效的底。我们发现 HF2-BE2 能高效地把 C 变换成 T,与直到在老鼠胚胎的 100% biallelic 变化效率。不同于 BE3, HF2-BE2 能在目标和非目标海滨上把 C 变换成 T,扩展基础编辑器的编辑范围。令人惊讶地,我们发现 HF2-BE2 能也使脱去氨基对 gRNA 有约束力的区域近似的 C。一起拿,我们的工作表明由基础编辑,和下划线在鼠标产生点变化的可行性小心地优化编辑系统以便消除近似地点的 deamination 的底的需要。 | Puping Liang Hongwei Sun Ying Sun Xiya Zhang Xiaowei Xie Jinran Zhang zhen Zhang Yuxi Chen Chenhui Ding Yuanyan Xiong Wenbin Ma Dan Liu Junjiu Huang Zhou Songyang | 2017 | Protein & Cell2017，8，8： | 17 |
| 4 | USP19 suppresses inflammation and promotes M2-like macrophage polarization by manipulating NLRP3 function via autophagy显示文摘Macrophage polarization to proinflammatory M1-like or anti-inflammatory M2-like cells is critical to mount a host defense or repair tissue.The exact molecular mechanisms controlling this process are still elusive.Here,we report that ubiquitin-specific protease 19(USP19)acts as an anti-inflammatory switch that inhibits inflammatory responses and promotes M2-like macrophage polarization.USP19 inhibited NLRP3 inflammasome activation by increasing autophagy flux and decreasing the generation of mitochondrial reactive oxygen species.In addition,USP19 inhibited the proteasomal degradation of inflammasome-independent NLRP3 by cleaving its polyubiquitin chains.USP19-stabilized NLRP3 promoted M2-like macrophage polarization by direct association with interferon regulatory factor 4,thereby preventing its p62-mediated selective autophagic degradation.Consistent with these observations,compared to wild-type mice,Usp19−/−mice had decreased M2-like macrophage polarization and increased interleukin-1βsecretion,in response to alum and chitin injections.Thus,we have uncovered an unexpected mechanism by which USP19 switches the proinflammatory function of NLRP3 into an anti-inflammatory function,and suggest that USP19 is a potential therapeutic target for inflammatory interventions. | Tao Liu Liqiu Wang Puping Liang Xiaojuan Wang Yukun Liu Jing Cai Yuanchu She Dan Wang Zhi Wang Zhiyong Guo Samuel Bates Xiaojun Xia Junjiu Huang Jun Cui | 2021 | Cellular & Molecular Immunology2021，18，10： | 15 |
| 5 | m6A RNA modification controls autophagy through upregulating ULK1 protein abundance显示文摘 | Shouheng Jin Xiya Zhang Yanyan Miao Puping Liang Kaiyu Zhu Yuanchu She Yaoxing Wu Di-Ao Liu Junjiu Huang Jian Ren Jun Cui | 2018 | Cell Research2018，28，9： | 12 |
| 6 | Effective and precise adenine base editing n mouse zygotes显示文摘 | Puping Liang Hongwei Sun Xiya Zhang Xiaowei Xie Jinran Zhang Yaofu Bai Xueling Ouyang Shengyao Zhi Yuanyan Xiong Wenbin Ma Dan Liu Junjiu Huang Zhou Songyang | 2018 | Protein & Cell2018，9，9： | 4 |
| 7 | HBB-deficient Macaca fascicularis monkey presents with human β-thalassemia显示文摘Dear Editor,β-Thalassemia is a common severe genetic disease caused by mutations in HBB and affects approximately 1.5% of the global population (Origa, 2017). In southern China, the carrier rate of β-thalassemia is as high as 6.43%, creating a high socio-economic burden (Xiong et al., 2010). In adult humans, there are three types of hemoglobin: HbA1 (~97%), HbA2 (~2%) and HbF (~1%). HbA1 (α2β2) is composed of two a-globin and two β-globi n sub units en coded by HBA and HBB, respectively;HbF (α2β2)is made up of two α-globin subunits and two β-globin sub units en coded by HBG. Mutations in the coding region or regulatory region of HBB are involved in β-thalassemia pathogenesis. Except for some rare dominant mutations, most HBB mutations are recessive (Origa, 2017). Depending on the mutation type, the β-globin level will either be reduced or completely depleted, resulting in α-globin accumulation and precipitation. These α-globin precipitates lead to red blood cell death, resulting in anemia and tissue damage, and even death in thalassemia major patients. Blood transfusions can help slow disease progression but lead to iron overload, ultimately resulting in iron toxicity. Bone marrow transfer is the only cure in the clinic and is available only to a small percentage of patients with human leukocyte antigervmatched donors. Recently, gene therapy and gene editing therapy have shown great promise in curing β-thalassemia (Glaser et al., 2015;Thompson et al., 2018). However, no appropriate animal models are available for evaluating the safety and efficacy of such advanced therapeutic strategies in vivo.β-thalassemia mice are the sole animal model available for research. However, substantial differences have been reported between the types and expressi on patter ns of human and mouse globins (McColl and Vadolas, 2016). Moreover, mice contain no fetal globin gene equivalent, and homozygous mutations of HBB in mouse for early models of β-thalassemia major or Cooley anemia are all embryonic lethal (Huo et al., 2009). Recently, significant phenotype and physiology differences have been reported between SIRT6- null mice and the non-human primate model (Zhang et al., 2018). Thus, an appropriate non-human primate model is needed for human β-thalassemia studies and treatments. | Yan Huang Chenhui Ding Puping Liang Duanduan Li Yu Tang Wei Meng Hongwei Sun Hongyu Lu Yu Chen Xueying Chen Qunshan Huang Jianpei Fang Canquan Zhou Shihua Yang Junjiu Huang | 2019 | Protein & Cell2019，10，7： | 4 |
| 8 | Telomere regulation in pluripotent stem cells显示文摘Pluripotent 干细胞(PSC ) 有潜力从所有三基本细菌层和能力生产房间的任何类型到自我更新并且在 vitro 无止境地增殖。PSC,胚胎的干细胞(转换字符) 和导致的 pluripotent 干细胞(iPSCs ) 的二种主要类型,分享象殖民地形态学, Oct4 和 Nanog 的高表示,和强壮的碱的磷酸酶活动那样的普通特征。在最近的年里,增加证据建议那 telomere 长度在维持干细胞 pluripotency 代表另一个重要内部因素。Telomere 长度动态平衡和它的结构的正直帮助保护染色体结束免受再结合,结束熔化,和 DNA 的伤害损坏回答,保证哺乳动物的房间的师的能力。PSC 通常展出高 telomerase 活动坚持说他们的极其长、稳定的 telomeres,和新兴的数据显示小径可以玩的 telomeres (中高音) 的其他的变长在 telomere 的一个重要角色也工作。如此的特征对他们在 vivo 区分进多样的房间类型的能力多半关键。在这评论,我们将在转换字符和 iPSCs 集中于 telomeres 的功能和规定,从而使 telomere 长度的重要性清楚些到在 PSC 调整 telomeres 的 pluripotency 和机制。 | Yan Huang Puping Liang Dan Liu Junjiu Huang Zhou Songyang | 2014 | Protein & Cell2014，5，3： | 3 |
| 9 | Homology-based repair induced by CRISPR-Cas nucleases in mammalian embryo genome editing显示文摘Recent advances in genome editing,especially CRISPR-Cas nucleases,have revolutionized both laboratory research and clinical therapeutics.CRISPR-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 diseases.HBR efficiency is highly dependent on the DNA donor that is utilized as a repair template.Here,we review recent progress in improving CRISPR-Cas nuclease-induced HBR in mammalian embryos by designing a suitable DNA donor.Moreover,we want to provide a guide for producing animal disease models and correcting genetic mutations through CRISPR-Cas nuclease-induced HBR in mammalian embryos.Finally,we discuss recent developments in precise genome-modification technology based on the CRISPR-Cas system. | Xiya Zhang Tao Li Jianping Ou Junjiu Huang Puping Liang | 2022 | Protein & Cell2022，13，5： | 3 |
| 10 | Production of non-mosaic genome edited porcine embryos by injection of CRISPR/Cas9 into germinal vesicle oocytes显示文摘Genetically modified pigs represent a great promise for generating models of human diseases and producing new breeds.Generation 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 transition.Injection of Cas9 mRNA and X-linked Dmd gene-specific gRNA into GV oocytes did not affect their developmental potential.The 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 maturation.Up to81.3% of the edited IVF embryos were non-mosaic Dmd gene mutant embryos.In conclusion,GVGE might be a valuable method for the generation of non-mosaic maternal allele edited FO embryos in a short simple step. | Xiaohu Su Wei Chen Qingqing Cai Puping Liang Yaosheng Chen Peiqing Cong Junjiu Huang | 2019 | Journal of Genetics and Genomics2019，46，7： | 2 |
| 11 | Effective generation of maternal genome point mutated porcine embryos by injection of cytosine base editor into germinal vesicle oocytes显示文摘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. | Xiaohu Su Wei Chen Qingqing Cai Puping Liang Yaosheng Chen Peiqing Cong Junjiu Huang | 2020 | Science China(Life Sciences)2020，63，7： | 1 |
| 12 | Cost-effective generation of A-to-G mutant mice by zygote electroporation of adenine base editor ribonucleoproteins显示文摘More than 32,000 pathogenic single nucleotide polymorphisms(SNPs)have been identified in the human genome(Gaudelli et al.,2017).Genetically modified mice with pathogenic SNPs are good models for studies of disease pathogenesis and the development of new therapeutics.Accordingly,an efficient,high-throughput method for the generation of mouse models with SNPs is needed. | Hongwei Sun Shengyao Zhi Guifang Wu Guanglan Wu Tianqi Cao Hu Hao Zhou Songyang Puping Liang Junjiu Huang | 2020 | Journal of Genetics and Genomics2020，47，6： | 1 |
| 13 | TRIM14通过抑制p62介导的cGAS的选择性自噬降解促进固有免疫反应显示文摘环GMP-AMP合成酶(cGAS)是细胞内识别DNA病毒,激活免疫反应的重要受体,但是对于它翻译后修饰的调控分子机制还不甚了解。 | Meixin Chen Qingcai Meng Yunfei Qin Puping Liang Peng Tan Lian He Yubin Zhou Yongjun Chen 黄军就 Rong-Fu Wang 崔隽 | 2017 | 科学新闻2017，19，4： | 0 |
| 14 | Systematic identification of CRISPR off-target effects by CROss-seq显示文摘DearEditor,The CRISPR-mediated genome editing tools,including nucleases,base editors(ABE/CBE),transposases/recombinases,and prime editor(PE),have been extensively applied in basic and clinical researches,although the off-target effect remains a major concern(Anzalone et al.,2020).Recently,various methods have been developed to assess the specificity and accuracy of different tools(Zhang et al.,2021),yet each method is designed for limited editing systems,and none of them can simultaneously detect off-target sites in vivo and in vitro.A versatile method for profiling genome-wide off-target effects of various tools remains lacking. | Yan Li Shengyao Zhi Tong Wu Hong-Xuan Chen Rui Kang Dong-Zhao Mai Zhou Songyang Chuan He Puping Liang Guan-Zheng Luo | 2023 | Protein & Cell2023，14，4： | 0 |
| 15 | Current therapies for osteoarthritis and prospects of CRISPR-based genome,epigenome,and RNA editing in osteoarthritis treatment显示文摘Osteoarthritis(OA)is one of the most common degenerative joint diseases worldwide,causing pain,disability,and decreased quality of life.The balance between regeneration and inflammation-induced degradation results in multiple etiologies and complex pathogenesis of OA.Currently,there is a lack of effective therapeutic strategies for OA treatment.With the development of CRISPR-based genome,epigenome,and RNA editing tools,OA treatment has been improved by targeting genetic risk factors,activating chondrogenic elements,and modulating inflammatory regulators.Supported by cell therapy and in vivo delivery vectors,genome,epigenome,and RNA editing tools may provide a promising approach for personalized OA therapy.This review summarizes CRISPR-based genome,epigenome,and RNA editing tools that can be applied to the treatment of OA and provides insights into the development of CRISPR-based therapeutics for OA treatment.Moreover,in-depth evaluations of the efficacy and safety of these tools in human OA treatment are needed. | Yuxi Chen Xiao Luo Rui Kang Kaixin Cui Jianping Ou Xiya Zhang Puping Liang | 2024 | Journal of Genetics and Genomics2024，51，2： | 0 |
| 16 | Correction of a CADASIL point mutation using adenine base editors in hiPsCsandbloodvessel organoids显示文摘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. | 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 | 2024 | Journal of Genetics and Genomics2024，51，2： | 0 |
| 17 | A novel undifferentiated spermatogonia-speci?c surface protein 1(USSP1) in neonatal mice显示文摘Mammalian spermatogenesis is maintained by a rare population of spermatogonial stem cells(SSCs),which are important for male fertility. SSCs remain a subset of undifferentiated spermatogonia, which can be isolated by a combination of surface markers. Specific markers to identify and isolate undifferentiated spermatogonia are lacking. Ussp1, a transcript previously annotated as long noncoding RNA(RIKEN cDNA 4933427D06, Gene ID: 232217), virtually encodes a membrane protein, USSP1, in a highly testisspecific manner in mouse. We demonstrate its expression on the membrane of undifferentiated spermatogonia by a homemade polyclonal rabbit antibody against the protein. In vivo, USSP1^+ clusters consist mainly of As, Apr(GFRa1^+) and Aal(PLZF^+) cells. USSP1^+ cells exhibit enrichment of undifferentiated spermatogonia, as shown by increased expression of SSC self-renewal molecular markers and the potential to form SSC clones in vitro and in vivo. However, Ussp1 knockout did not affect the number of SSCs or spermatogenesis in mice. Thy1^+ cells from Ussp1 null mice did not show any defect in the SSC colony formation capacity, indicating that USSP1 is not essential for SSC self-renewal. Our data demonstrate that Ussp1 is specifically expressed in undifferentiated murine spermatogonia, indicating the potential to sort undifferentiated spermatogonia with USSP1 antibodies. Ussp1 might be a good maker for SSC enrichment in neonatal mice. | Zhuoheng Lin Puping Liang Zhaokai Yao Yuxi Chen Xiya Zhang Rui Huang Zhen Zhang Minyan Li Wenbin Ma Haiyan Zheng Shanbo Cao Guang Shi Xiaoyang Zhao Zhou Songyang Junjiu Huang | 2019 | Science Bulletin2019，64，8： | 0 |
| 18 | CRISPR-assisted transcription activation by phaseseparation proteins显示文摘The clustered regularly interspaced short palindromic repeats(CRISPR)-Cas9 system has been widely used for genome engineering and transcriptional regulation in many different organisms.Current CRISPR-activation(CRISPRa)platforms often require multiple components because of inefficient transcriptional activation.Here,we fused different phase-separation proteins to dCas9-VPR(dCas9-VP64-P65-RTA)and observed robust increases in transcriptional activation efficiency.Notably,human NUP98(nucleoporin 98)and FUS(fused in sarcoma)IDR domains were best at enhancing dCas9-VPR activity,with dCas9-VPR-FUS IDR(VPRF)outperforming the other CRISPRa systems tested in this study in both activation efficiency and system simplicity.dCas9-VPRF overcomes the target strand bias and widens gRNA designing windows without affecting the off-target effect of dCas9-VPR.These findings demonstrate the feasibility of using phase-separation proteins to assist in the regulation of gene expression and support the broad appeal of the dCas9-VPRF system in basic and clinical applications. | Jiaqi Liu Yuxi Chen Baoting Nong Xiao Luo Kaixin Cui Zhan Li Pengfei Zhang Wenqiong Tan Yue Yang Wenbin Ma Puping Liang Zhou Songyang | 2023 | Protein & Cell2023，14，12： | 0 |
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