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ZEB1 Induces Ddr1 Promoter Hypermethylation and Contributes to the Chronic Pain in Spinal Cord in Rats Following Oxaliplatin Treatment

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Abstract

Application of chemotherapeutic oxaliplatin represses gene transcription through induction of DNA methylation, which may contribute to oxaliplatin-induced chronic pain. Here, Ddr1, which showed an increased methylation in the promoter, was screened from the SRA methylation database (PRJNA587622) after oxaliplatin treatment. qPCR and MeDIP assays verified that oxaliplatin treatment increased the methylation in Ddr1 promoter region and decreased the expression of DDR1 in the neurons of spinal dorsal horn. In addition, overexpression of DDR1 by intraspinal injection of AAV-hSyn-Ddr1 significantly alleviated the mechanical allodynia induced by oxaliplatin. Furthermore, we found that oxaliplatin treatment increased the expression of DNMT3b and ZEB1 in dorsal horn neurons, and promoted the interaction between DNMT3b and ZEB1. Intrathecal injection of ZEB1 siRNA inhibited the enhanced recruitment of DNMT3b and the hypermethylation in Ddr1 promoter induced by oxaliplatin. Finally, ZEB1 siRNA rescued the DDR1 downregulation and mechanical allodynia induced by oxaliplatin. In conclusion, these results suggested that the ZEB1 recruited DNMT3b to the Ddr1 promoter, which induced the DDR1 downregulation and contributed to the oxaliplatin-induced chronic pain.

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Data Availability

The analyzed data sets generated during the present study are available from the corresponding author on reasonable request.

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Funding

This study was supported by National Natural Science Foundation of China (31970936, 81801103, 81971048, 81901127); Natural Science Foundation of Guangdong Province (2019A1515010871, 2019A1515010645); Shanghai Pujiang Program (2020PJD059).

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Author notes

  1. Yi-Ying Chen, Kai-Sheng Jiang and Xiao-Hui Bai have equal contribution to this work.

Authors and Affiliations

  1. Sun Yat-Sen Medical School and Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, Guangzhou, 510080, China

    Yi-Ying Chen, Kai-Sheng Jiang, Meng Liu, Su-Yan Lin, Ting Xu & Wen-Jun Xin

  2. Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, 510080, China

    Xiao-Hui Bai

  3. Guangdong Provincial Key Laboratory of Biomedical Imaging, Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China

    Jia-You Wei

  4. Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China

    Dai Li & Yuan-Chang Xiong

  5. Department of Emergency Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Sun Yet-Sen University, 58 Zhongshan Rd. 2, Guangzhou, 510080, China

    Zhen-Yu Li

Authors
  1. Yi-Ying Chen
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Y-YC, K-SJ, X-HB, ML, S-YL, TX, J-YW, DL, Y-CX and W-JX. The first draft of the manuscript was written by Z-YL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Zhen-Yu Li.

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All experimental protocols were approved by the Local Animal Care Committee and carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Chen, YY., Jiang, KS., Bai, XH. et al. ZEB1 Induces Ddr1 Promoter Hypermethylation and Contributes to the Chronic Pain in Spinal Cord in Rats Following Oxaliplatin Treatment. Neurochem Res 46, 2181–2191 (2021). https://doi.org/10.1007/s11064-021-03355-5

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