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Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons

Author

Listed:
  • Dalia Halawani

    (Icahn School of Medicine at Mount Sinai)

  • Yiqun Wang

    (Icahn School of Medicine at Mount Sinai
    Second Affiliated Hospital of Xi’an Jiaotong University)

  • Aarthi Ramakrishnan

    (Icahn School of Medicine at Mount Sinai)

  • Molly Estill

    (Icahn School of Medicine at Mount Sinai)

  • Xijing He

    (Second Affiliated Hospital of Xi’an Jiaotong University
    Xi’an International Medical Center Hospital)

  • Li Shen

    (Icahn School of Medicine at Mount Sinai)

  • Roland H. Friedel

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Hongyan Zou

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

Abstract

Axon regeneration of dorsal root ganglia (DRG) neurons after peripheral axotomy involves reconfiguration of gene regulatory circuits to establish regenerative gene programs. However, the underlying mechanisms remain unclear. Here, through an unbiased survey, we show that the binding motif of Bmal1, a central transcription factor of the circadian clock, is enriched in differentially hydroxymethylated regions (DhMRs) of mouse DRG after peripheral lesion. By applying conditional deletion of Bmal1 in neurons, in vitro and in vivo neurite outgrowth assays, as well as transcriptomic profiling, we demonstrate that Bmal1 inhibits axon regeneration, in part through a functional link with the epigenetic factor Tet3. Mechanistically, we reveal that Bmal1 acts as a gatekeeper of neuroepigenetic responses to axonal injury by limiting Tet3 expression and restricting 5hmC modifications. Bmal1-regulated genes not only concern axon growth, but also stress responses and energy homeostasis. Furthermore, we uncover an epigenetic rhythm of diurnal oscillation of Tet3 and 5hmC levels in DRG neurons, corresponding to time-of-day effect on axon growth potential. Collectively, our studies demonstrate that targeting Bmal1 enhances axon regeneration.

Suggested Citation

  • Dalia Halawani & Yiqun Wang & Aarthi Ramakrishnan & Molly Estill & Xijing He & Li Shen & Roland H. Friedel & Hongyan Zou, 2023. "Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40816-7
    DOI: 10.1038/s41467-023-40816-7
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    References listed on IDEAS

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    1. Elga Esposito & Wenlu Li & Emiri T. Mandeville & Ji-Hyun Park & Ikbal Şencan & Shuzhen Guo & Jingfei Shi & Jing Lan & Janice Lee & Kazuhide Hayakawa & Sava Sakadžić & Xunming Ji & Eng H. Lo, 2020. "Author Correction: Potential circadian effects on translational failure for neuroprotection," Nature, Nature, vol. 583(7814), pages 14-14, July.
    2. Elga Esposito & Wenlu Li & Emiri T. Mandeville & Ji-Hyun Park & Ikbal Şencan & Shuzhen Guo & Jingfei Shi & Jing Lan & Janice Lee & Kazuhide Hayakawa & Sava Sakadžić & Xunming Ji & Eng H. Lo, 2020. "Potential circadian effects on translational failure for neuroprotection," Nature, Nature, vol. 582(7812), pages 395-398, June.
    3. Chang Liu & Siming Li & Tiecheng Liu & Jimo Borjigin & Jiandie D. Lin, 2007. "Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism," Nature, Nature, vol. 447(7143), pages 477-481, May.
    4. Wei Wu & Sarah E. Hill & William J. Nathan & Jacob Paiano & Elsa Callen & Dongpeng Wang & Kenta Shinoda & Niek Wietmarschen & Jennifer M. Colón-Mercado & Dali Zong & Raffaella Pace & Han-Yu Shih & Ste, 2021. "Neuronal enhancers are hotspots for DNA single-strand break repair," Nature, Nature, vol. 593(7859), pages 440-444, May.
    5. Oshri Avraham & Pan-Yue Deng & Sara Jones & Rejji Kuruvilla & Clay F. Semenkovich & Vitaly A. Klyachko & Valeria Cavalli, 2020. "Satellite glial cells promote regenerative growth in sensory neurons," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    6. Gabriel Oh & Sasha Ebrahimi & Matthew Carlucci & Aiping Zhang & Akhil Nair & Daniel E. Groot & Viviane Labrie & Peixin Jia & Edward S. Oh & Richie H. Jeremian & Miki Susic & Tenjin C. Shrestha & Marti, 2018. "Cytosine modifications exhibit circadian oscillations that are involved in epigenetic diversity and aging," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    7. Radhika Puttagunta & Andrea Tedeschi & Marilia Grando Sória & Arnau Hervera & Ricco Lindner & Khizr I. Rathore & Perrine Gaub & Yashashree Joshi & Tuan Nguyen & Antonio Schmandke & Claudia J. Laskowsk, 2014. "PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system," Nature Communications, Nature, vol. 5(1), pages 1-13, May.
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