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Methylation silencing and reactivation of exogenous genes in lentivirus-mediated transgenic mice

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DOI

  • Jinkun Wen, Sun Yat-Sen University
  • ,
  • Jinni Wu, Sun Yat-Sen University
  • ,
  • Tianqi Cao, Sun Yat-Sen University
  • ,
  • Shengyao Zhi, Sun Yat-Sen University
  • ,
  • Yuxi Chen, Sun Yat-Sen University
  • ,
  • Lars Aagaard
  • Peilin Zhen, Sun Yat-Sen University
  • ,
  • Yanming Huang, Sun Yat-Sen University
  • ,
  • Jianxin Zhong, Sun Yat-Sen University
  • ,
  • Junjiu Huang, Sun Yat-Sen University

Taking advantage of their ability to integrate their genomes into the host genome, lentiviruses have been used to rapidly produce transgenic mice in biomedical research. In most cases, transgenes delivered by lentiviral vectors have resisted silencing mediated by epigenetic modifications in mice. However, some studies revealed that methylation caused decreased transgene expression in mice. Therefore, there is conflicting evidence regarding the methylation-induced silencing of transgenes delivered by lentiviral transduction in mice. In this study, we present evidence that the human TTR transgene was silenced by DNA methylation in the liver of a transgenic mouse model generated by lentiviral transduction. The density of methylation on the transgene was increased during reproduction, and the expression of the transgene was completely silenced in mice of the F2 generation. Interestingly, 5-azacytidine (5-AzaC), a methyltransferase inhibitor, potently reactivated the silenced genes in neonatal mice whose hepatocytes were actively proliferating and led to stable transgene expression during development. However, 5-AzaC did not rescue liver transgene expression when administered to adult mice. Moreover, 5-AzaC at the given dose had low developmental toxicity in the newborn mice. In summary, we demonstrate the methylation-induced silencing of an exogenous gene in the liver of a mouse model generated by lentiviral transduction and show that the silenced transgene can be safely and efficiently reactivated by 5-AzaC treatment, providing an alternative way to obtain progeny with stable transgene expression in the case of the methylation of exogenous genes in transgenic mice generated by lentiviral transduction.

OriginalsprogEngelsk
TidsskriftTransgenic Research
Vol/bind30
Nummer1
Sider (fra-til)63-76
Antal sider14
ISSN0962-8819
DOI
StatusUdgivet - feb. 2021

Bibliografisk note

Funding Information:
This study was funded by the National Key R&D Program of China (2017YFC1001901), the National Natural Science Foundation of China (31971365 and 31671540), the Guangzhou Science and Technology Project (201803010020), the Guangdong Special Support Program (2019BT02Y276), the Guangdong Basic and Applied Basic Research Foundation (2019A1515010600), the Project funded by China Postdoctoral Science Foundation (2019M653205) and the Fundamental Research Funds for the Central Universities (19lgpy195).

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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