Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons
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 o...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-08-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40816-7 |
| _version_ | 1797558008462442496 |
|---|---|
| author | Dalia Halawani Yiqun Wang Aarthi Ramakrishnan Molly Estill Xijing He Li Shen Roland H. Friedel Hongyan Zou |
| author_facet | Dalia Halawani Yiqun Wang Aarthi Ramakrishnan Molly Estill Xijing He Li Shen Roland H. Friedel Hongyan Zou |
| author_sort | Dalia Halawani |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:25:18Z |
| format | Article |
| id | doaj.art-66436afe3fff457c990dac6982d2545e |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:25:18Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-66436afe3fff457c990dac6982d2545e2023-11-20T10:12:34ZengNature PortfolioNature Communications2041-17232023-08-0114112210.1038/s41467-023-40816-7Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neuronsDalia Halawani0Yiqun Wang1Aarthi Ramakrishnan2Molly Estill3Xijing He4Li Shen5Roland H. Friedel6Hongyan Zou7Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiDepartment of Orthopedics, Second Affiliated Hospital of Xi’an Jiaotong UniversityNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount SinaiAbstract 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.https://doi.org/10.1038/s41467-023-40816-7 |
| spellingShingle | Dalia Halawani Yiqun Wang Aarthi Ramakrishnan Molly Estill Xijing He Li Shen Roland H. Friedel Hongyan Zou Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons Nature Communications |
| title | Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons |
| title_full | Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons |
| title_fullStr | Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons |
| title_full_unstemmed | Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons |
| title_short | Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons |
| title_sort | circadian clock regulator bmal1 gates axon regeneration via tet3 epigenetics in mouse sensory neurons |
| url | https://doi.org/10.1038/s41467-023-40816-7 |
| work_keys_str_mv | AT daliahalawani circadianclockregulatorbmal1gatesaxonregenerationviatet3epigeneticsinmousesensoryneurons AT yiqunwang circadianclockregulatorbmal1gatesaxonregenerationviatet3epigeneticsinmousesensoryneurons AT aarthiramakrishnan circadianclockregulatorbmal1gatesaxonregenerationviatet3epigeneticsinmousesensoryneurons AT mollyestill circadianclockregulatorbmal1gatesaxonregenerationviatet3epigeneticsinmousesensoryneurons AT xijinghe circadianclockregulatorbmal1gatesaxonregenerationviatet3epigeneticsinmousesensoryneurons AT lishen circadianclockregulatorbmal1gatesaxonregenerationviatet3epigeneticsinmousesensoryneurons AT rolandhfriedel circadianclockregulatorbmal1gatesaxonregenerationviatet3epigeneticsinmousesensoryneurons AT hongyanzou circadianclockregulatorbmal1gatesaxonregenerationviatet3epigeneticsinmousesensoryneurons |