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Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on opiate-induced synaptic and behavioral plasticity

Molecular Psychiatry volume 26, pages 1162–1177 (2021)Cite this article

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Abstract

Compelling evidence suggests that synaptic structural plasticity, driven by remodeling of the actin cytoskeleton, underlies addictive drugs-induced long-lasting behavioral plasticity. However, the signaling mechanisms leading to actin cytoskeleton remodeling remain poorly defined. DNA methylation is a critical mechanism used to control activity-dependent gene expression essential for long-lasting synaptic plasticity. Here, we provide evidence that DNA methyltransferase DNMT3a is degraded by the E2 ubiquitin-conjugating enzyme Ube2b-mediated ubiquitination in dorsal hippocampus (DH) of rats that repeatedly self-administrated heroin. DNMT3a degradation leads to demethylation in CaMKK1 gene promotor, thereby facilitating CaMKK1 expression and consequent activation of its downstream target CaMKIα, an essential regulator of spinogenesis. CaMKK1/CaMKIα signaling regulates actin cytoskeleton remodeling in the DH and behavioral plasticity by activation of Rac1 via acting Rac guanine-nucleotide-exchange factor βPIX. These data suggest that Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on CaMKK1 gene and thus activates CaMKK1/CaMKIα/βPIX/Rac1 cascade, leading to drug use-induced actin polymerization and behavior plasticity.

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Acknowledgements

This research was supported by grants 2015CB553502 (to J-GL) from the Ministry of Science and Technology of China, by grants 81130087, 81671322 (to J-GL) and 81773710 (to Y-JW) from National Natural Science Foundation of China, by grant 2017334 (to Y-JW) from the Youth Innovation Promotion Association of the Chinese Academy of Sciences, and by grant 2015M570392 (to Z-GC) from China Postdoctoral Science Foundation.

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  1. These authors contributed equally: Zhong-Guo Chen, Yu-Jun Wang, Ruo-Song Chen

Authors and Affiliations

  1. Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Zhong-Guo Chen, Yu-Jun Wang, Ruo-Song Chen, Wei-Sheng Wang, Xing Liu, Hu Zhou & Jing-Gen Liu

  2. Department of Pharmacology, China Pharmaceutical University, Nanjing, 210008, China

    Zhong-Guo Chen, Chen-Ling Gan, Ling He & Jing-Gen Liu

  3. Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, China

    Zhong-Guo Chen, Fan Geng & Gang Hu

  4. University of Chinese Academy of Sciences, Shanghai, 200031, China

    Ruo-Song Chen & Jing-Gen Liu

  5. Department of Neurobiology and Acupuncture, The Third Clinic Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurobiology of Zhejiang Province, Hangzhou, 310053, China

    Jing-Gen Liu

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Contributions

J-GL and Z-GC designed the experiments. Z-GC, Y-JW, R-SC, FG, and C-LG performed the experiments with the assistance of W-SW, XL, and HZ. Statistical data analysis was performed by Z-GC, J-GL, and GH supervised the study. This manuscript was written by Z-GC, and re-written by Y-JW and J-GL. Funding Acquisition, J-GL, Y-JW, and Z-GC.

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Correspondence to Gang Hu or Jing-Gen Liu.

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Chen, ZG., Wang, YJ., Chen, RS. et al. Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on opiate-induced synaptic and behavioral plasticity. Mol Psychiatry 26, 1162–1177 (2021). https://doi.org/10.1038/s41380-019-0533-y

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