Protein & Cell >

2020 , Vol. 11 >Issue 11: 809 - 824

DOI: https://doi.org/10.1007/s13238-020-00740-8

RESEARCH ARTICLE

Generation of a Hutchinson–Gilford progeria syndrome monkey model by base editing

  • Fang Wang 1,2 ,
  • Weiqi Zhang 3,4,5,6 ,
  • Qiaoyan Yang 7 ,
  • Yu Kang 1 ,
  • Yanling Fan 4,5 ,
  • Jingkuan Wei 1 ,
  • Zunpeng Liu 6,8 ,
  • Shaoxing Dai 1 ,
  • Hao Li 4,5,6 ,
  • Zifan Li 1 ,
  • Lizhu Xu 1 ,
  • Chu Chu 1,2 ,
  • Jing Qu 3,6,8 ,
  • Chenyang Si 1,2 ,
  • Weizhi Ji , 1 ,
  • Guang-Hui Liu , 3,6,9,10 ,
  • Chengzu Long , 7,11,12 ,
  • Yuyu Niu , 1,2
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  • 1. Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China
  • 2. Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
  • 3. Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing 100101, China
  • 4. CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
  • 5. China National Center for Bioinformation, Beijing 100101, China
  • 6. University of Chinese Academy of Sciences, Beijing 100049, China
  • 7. The Leon H Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA
  • 8. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
  • 9. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
  • 10. Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
  • 11. Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA
  • 12. Department of Neurology, New York University School of Medicine, New York, NY 10016, USA

Received date: 09 Apr 2020

Accepted date: 11 May 2020

Published date: 15 Nov 2020

Copyright

2020 The Author(s)
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Abstract

Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions. Here, we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA (gRNA) targeting the LMNA gene via microinjection into monkey zygotes. Five out of six newborn monkeys carried the mutation specifically at the target site. HGPS monkeys expressed the toxic form of lamin A, progerin, and recapitulated the typical HGPS phenotypes including growth retardation, bone alterations, and vascular abnormalities. Thus, this monkey model genetically and clinically mimics HGPS in humans, demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.

Key words： base editing; non-human primate; HGPS

Cite this article

Fang Wang , Weiqi Zhang , Qiaoyan Yang , Yu Kang , Yanling Fan , Jingkuan Wei , Zunpeng Liu , Shaoxing Dai , Hao Li , Zifan Li , Lizhu Xu , Chu Chu , Jing Qu , Chenyang Si , Weizhi Ji , Guang-Hui Liu , Chengzu Long , Yuyu Niu . Generation of a Hutchinson–Gilford progeria syndrome monkey model by base editing[J]. Protein & Cell, 2020 , 11(11) : 809 -824 . DOI: 10.1007/s13238-020-00740-8

References

Publishing order | Descend order by publishing year | Descend order by cited within
1
Aktas S, Kiyak M, Ozdil K, Kurtca I, Kibar S, Ahbab S, Karadeniz Y, Saler T (2013) Gastrointestinal tract hemorrhage due to angiodysplasia in hutchinson gilfort Progeria syndrome. J Med Cases 4(8):576–578

DOI

2
Anders S, Pyl PT, Huber W (2015) HTSeq–a Python framework to work with high-throughput sequencing data. Bioinformatics 31:166–169

DOI

3
Bae S, Park J, Kim JS (2014) Cas-OFFinder: a fast and versatile algorithm that searches for potential off-target sites of Cas9 RNAguided endonucleases. Bioinformatics 30:1473–1475

DOI

4
Capell BC, Collins FS (2006) Human laminopathies: nuclei gone genetically awry. Nat Rev Genet 7:940–952

DOI

5
Chan AWS (2013) Progress and prospects for genetic modification of nonhuman primate models in biomedical research. ILAR J 54:211–223

DOI

6
Chen S, Zhou Y, Chen Y, Gu J (2018) fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34:i884–i890

DOI

7
Chu Y, Xu Z-G, Xu Z, Ma L (2015) Hutchinson-Gilford progeria syndrome caused by an LMNA mutation: a case report. Pediatr Dermatol 32:271–275

DOI

8
Debacq-Chainiaux F, Erusalimsky JD, Campisi J, Toussaint O (2009) Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc 4:1798–1806

DOI

9
Ding Z, Sui L, Ren R, Liu Y, Xu X, Fu L, Bai R, Yuan T, Hao Y, Zhang W (2015) A widely adaptable approach to generate integration-free iPSCs from non-invasively acquired human somatic cells. Protein Cell 6:386–389

DOI

10
Dorado B, Ploen GG, Barettino A, Macias A, Gonzalo P, AndresManzano MJ, Gonzalez-Gomez C, Galan-Arriola C, Alfonso JM, Lobo M (2019) Generation and characterization of a novel knockin minipig model of Hutchinson–Gilford progeria syndrome. Cell Discov 5:16

DOI

11
Doubaj Y, Lamzouri A, Elalaoui SC, Laarabi FZ, Sefiani A (2011) Syndrome d’Hutchinson-Gilford (progéria). À propos de 3 cas. Archives de Pédiatrie 18:156–159

DOI

12
Erdem N, Güneş AT, Avcı O, Osma E (1994) A case of Hutchinson– Gilford progeria syndrome mimicking scleredema in early infancy. Dermatology 188:318–321

DOI

13
Fleischer JG, Schulte R, Tsai HH, Tyagi S, Ibarra A, Shokhirev MN, Huang L, Hetzer MW, Navlakha S (2018) Predicting age from the transcriptome of human dermal fibroblasts. Genome Biol 19:221

DOI

14
Giangreco A, Qin M, Pintar JE, Watt FM (2008) Epidermal stem cells are retained in vivo throughout skin aging. Aging Cell 7:250–259

DOI

15
Gordon CM, Gordon LB, Snyder BD, Nazarian A, Quinn N, Huh S, Giobbie-Hurder A, Neuberg D, Cleveland R, Kleinman M (2011) Hutchinson–gilford progeria is a skeletal dysplasia. J Bone Miner Res 26:1670–1679

DOI

16
Gordon LB, Harten IA, Patti ME, Lichtenstein AH (2005) Reduced adiponectin and HDL cholesterol without elevated C-reactive protein: clues to the biology of premature atherosclerosis in Hutchinson–Gilford progeria syndrome. J Pediatr 146:336–341

DOI

17
Gordon Leslie B, Kleinman Monica E, Massaro J, D’Agostino Ralph B, Shappell H, Gerhard-Herman M, Smoot Leslie B, Gordon Catherine M, Cleveland Robert H, Nazarian A (2016) Clinical trial of the protein farnesylation inhibitors lonafarnib, pravastatin, and zoledronic acid in children with Hutchinson–Gilford progeria syndrome. Circulation 134:114–125

DOI

18
Hennekam RCM (2006) Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A 140A:2603–2624

DOI

19
Jung H-J, Coffinier C, Choe Y, Beigneux AP, Davies BSJ, Yang SH, Barnes RH, Hong J, Sun T, Pleasure SJ (2012) Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA. Proc Natl Acad Sci USA 109:E423–E431

DOI

20
Kang Y, Chu C, Wang F, Niu Y (2019) CRISPR/Cas9-mediated genome editing in nonhuman primates. Dis Models Mech 12:39982

DOI

21
Khalifa MM (1989) Hutchinson-Gilford progeria syndrome: report of a Libyan family and evidence of autosomal recessive inheritance. Clin Genet 35:125–132

DOI

22
Kim D, Langmead B, Salzberg SL (2015) HISAT: a fast spliced aligner with low memory requirements. Nat Methods 12:357–360

DOI

23
Kim K, Ryu S-M, Kim S-T, Baek G, Kim D, Lim K, Chung E, Kim S, Kim J-S (2017) Highly efficient RNA-guided base editing in mouse embryos. Nat Biotechnol 35:435

DOI

24
Kim S, Scheffler K, Halpern AL, Bekritsky MA, Noh E, Kallberg M, Chen X, Kim Y, Beyter D, Krusche P (2018) Strelka2: fast and accurate calling of germline and somatic variants. Nat Methods 15:591–594

DOI

25
Koblan LW, Doman JL, Wilson C, Levy JM, Tay T, Newby GA, Maianti JP, Raguram A, Liu DR (2018a) Improving cytidine and adenine base editors by expression optimization and ancestral reconstruction. Nat Biotechnol 36:843–846

DOI

26
Koblan LW, Doman JL, Wilson C, Levy JM, Tay T, Newby GA, Maianti JP, Raguram A, Liu DR (2018b) Improving cytidine and adenine base editors by expression optimization and ancestral reconstruction. Nat Biotechnol 36:843–846

DOI

27
Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR (2016) Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533:420

DOI

28
Korf B (2008) Hutchinson–Gilford progeria syndrome, aging, and the nuclear lamina. N Engl J Med 358:552–555

DOI

29
Kubben N, Zhang W, Wang L, Voss TC, Yang J, Qu J, Liu GH, Misteli T (2016) Repression of the antioxidant NRF2 pathway in premature aging. Cell 165:1361–1374

DOI

30
Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Hoover J (2016) ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res 44:D862–D868

DOI

31
Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25:1754–1760

DOI

32
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, Genome Project Data Processing, S (2009) The sequence alignment/map format and SAMtools. Bioinformatics 25:2078–2079

DOI

33
Liang P, Ding C, Sun H, Xie X, Xu Y, Zhang X, Sun Y, Xiong Y, Ma W, Liu Y (2017) Correction of β-thalassemia mutant by base editor in human embryos. Protein Cell 8:811–822

DOI

34
Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang SL, Panopoulos AD, Suzuki K, Kurian L, Walsh C (2011a) Recapitulation of premature ageing with iPSCs from Hutchinson–Gilford progeria syndrome. Nature 472:221–225

DOI

35
Liu GH, Suzuki K, Qu J, Sancho-Martinez I, Yi F, Li M, Kumar S, Nivet E, Kim J, Soligalla RD (2011b) Targeted gene correction of laminopathy-associated LMNA mutations in patientspecific iPSCs. Cell Stem Cell 8:688–694

DOI

36
Liu Z, Chen M, Chen S, Deng J, Song Y, Lai L, Li Z (2018a) Highly efficient RNA-guided base editing in rabbit. Nat Commun 9:2717

DOI

37
Liu Z, Chen M, Chen S, Deng J, Song Y, Lai L, Li Z (2018b) Highly efficient RNA-guided base editing in rabbit. Nat Commun 9:2717

DOI

38
Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550

DOI

39
Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith ACM, Perry MB, Brewer CC, Zalewski C, Kim HJ, Solomon B (2008) Phenotype and course of Hutchinson–Gilford progeria syndrome. N Engl J Med 358:592–604

DOI

40
Monu JUV, Benka-Coker LBO, Fatunde Y (1990) Hutchinson– Gilford progeria syndrome in siblings. Skeletal Radiol 19:585–590

DOI

41
National Genomics Data Center, M., and Partners (2020) Database Resources of the National Genomics Data Center in 2020. Nucleic Acids Res 48:D24–D33

42
Niu Y, Yu Y, Bernat A, Yang S, He X, Guo X, Chen D, Chen Y, Ji S, Si W (2010) Transgenic rhesus monkeys produced by gene transfer into early-cleavage-stage embryos using a simian immunodeficiency virus-based vector. Proc Natl Acad Sci USA 107:17663–17667

DOI

43
Osorio FG, Navarro CL, Cadinanos J, Lopez-Mejia IC, Quiros PM, Bartoli C, Rivera J, Tazi J, Guzman G, Varela I (2011) Splicing-directed therapy in a new mouse model of human accelerated aging. Sci Transl Med 3:106ra107

DOI

44
Ozonoff MB, Clemett AR (1967) Progressive osteolysis in progeria. Am J Roentgenol 100:75–79

DOI

45
Pickar-Oliver A, Gersbach CA (2019) The next generation of CRISPR–Cas technologies and applications. Nat Rev Mol Cell Biol 20:490–507

DOI

46
Prakash A, Gordon LB, Kleinman ME, Gurary EB, Massaro J, D’Agostino R Sr, Kieran MW, Gerhard-Herman M, Smoot L (2018) Cardiac abnormalities in patients with Hutchinson–Gilford progeria syndrome. JAMA Cardiol 3:326–334

DOI

47
Rastogi R, Chander Mohan S (2008) Progeria syndrome: a case report. Indian J Orthopaedics 42:97–99

DOI

48
Rivera-Torres J, Calvo CJ, Llach A, Guzmán-Martínez G, Caballero R, González-Gómez C, Jiménez-Borreguero LJ, Guadix JA, Osorio FG, López-Otín C (2016) Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations. Proc Natl Acad Sci USA 113:E7250–E7259

DOI

49
Rork JF, Huang JT, Gordon LB, Kleinman M, Kieran MW, Liang MG (2014) Initial cutaneous manifestations of Hutchinson–Gilford progeria syndrome. Pediatr Dermatol 31:196–202

DOI

50
Selvin E, Najjar SS, Cornish TC, Halushka MK (2010) A comprehensive histopathological evaluation of vascular medial fibrosis: insights into the pathophysiology of arterial stiffening. Atherosclerosis 208:69–74

DOI

51
Silvera VM, Gordon LB, Orbach DB, Campbell SE, Machan JT, Ullrich NJ (2013) Imaging characteristics of cerebrovascular arteriopathy and stroke in Hutchinson-Gilford progeria syndrome. Am J Neuroradiol 34:1091–1097

DOI

52
Stehbens WE, Wakefield SJ, Gilbert-Barness E, Olson RE, Ackerman J (1999) Histological and ultrastructural features of atherosclerosis in progeria. Cardiovasc Pathol 8:29–39

DOI

53
Tarasov A, Vilella AJ, Cuppen E, Nijman IJ, Prins P (2015) Sambamba: fast processing of NGS alignment formats. Bioinformatics 31:2032–2034

DOI

54
Ullrich NJ, Gordon LB (2015) Chapter 18 – Hutchinson–Gilford progeria syndrome. In: Islam MP, Roach ES (eds) Handbook of clinical neurology. Elsevier, Amsterdam, pp 249–264

DOI

55
Ullrich NJ, Silvera VM, Campbell SE, Gordon LB (2012) Craniofacial abnormalities in Hutchinson–Gilford progeria syndrome. Am J Neuroradiol 33:1512–1518

DOI

56
Wang Y, Song F, Zhu J, Zhang S, Yang Y, Chen T, Tang B, Dong L, Ding N, Zhang Q (2017) GSA: genome sequence archive. Genomics Proteomics Bioinform 15:14–18

DOI

57
Wei Q, Zhan X, Zhong X, Liu Y, Han Y, Chen W, Li B (2015) A Bayesian framework for de novo mutation calling in parentsoffspring trios. Bioinformatics 31:1375–1381

DOI

58
Wu Z, Zhang W, Song M, Wang W, Wei G, Li W, Lei J, Huang Y, Sang Y, Chan P (2018) Differential stem cell aging kinetics in Hutchinson–Gilford progeria syndrome and Werner syndrome. Protein Cell 9:333–350

DOI

59
Xu S, Jin Z-G (2019) Hutchinson–Gilford progeria syndrome: cardiovascular pathologies and potential therapies. Trends Biochem Sci 44:561–564

DOI

60
Zhang M, Zhou C, Wei Y, Xu C, Pan H, Ying W, Sun Y, Sun Y, Xiao Q, Yao N (2019a) Human cleaving embryos enable robust homozygotic nucleotide substitutions by base editors. Genome Biol 20:101

DOI

61
Zhang W, Wan H, Feng G, Qu J, Wang J, Jing Y, Ren R, Liu Z, Zhang L, Chen Z (2018) SIRT6 deficiency results in developmental retardation in cynomolgus monkeys. Nature 560:661–665

DOI

62
Zhang X, Liu Z, Liu X, Wang S, Zhang Y, He X, Sun S, Ma S, ShyhChang N, Liu F (2019b) Telomere-dependent and telomereindependent roles of RAP1 in regulating human stem cell homeostasis. Protein Cell 10:649–667

DOI

63
Zhou C, Zhang M, Wei Y, Sun Y, Sun Y, Pan H, Yao N, Zhong W, Li Y, Li W (2017) Highly efficient base editing in human tripronuclear zygotes. Protein Cell 8:772–775

DOI

64
Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C, Chanda SK (2019) Metascape provides a biologistoriented resource for the analysis of systems-level datasets. Nat Commun 10:1523

DOI

65
Zuo E, Sun Y, Wei W, Yuan T, Ying W, Sun H, Yuan L, Steinmetz LM, Li Y, Yang H (2019) Cytosine base editor generates substantial off-target single-nucleotide variants in mouse embryos. Science. 364(6437):289

DOI

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