Abstract
Schwann cells play a critical role after peripheral nerve injury by clearing myelin debris, forming axon-guiding bands of Büngner, and remyelinating regenerating axons. Schwann cells undergo epigenomic remodeling to differentiate into a repair state that expresses unique genes, some of which are not expressed at other stages of Schwann cell development. We previously identified a set of enhancers that are activated in Schwann cells after nerve injury, and we determined whether these enhancers are preprogrammed into the Schwann cell epigenome as poised enhancers before injury. Poised enhancers share many attributes of active enhancers, such as open chromatin, but are marked by repressive histone H3 lysine 27 (H3K27) trimethylation rather than H3K27 acetylation. We find that most injury-induced enhancers are not marked as poised enhancers before injury indicating that injury-induced enhancers are not preprogrammed in the Schwann cell epigenome. Injury-induced enhancers are enriched with AP-1 binding motifs, and the c-JUN subunit of AP-1 had been shown to be critical to drive the transcriptional response of Schwann cells after injury. Using in vivo chromatin immunoprecipitation sequencing analysis in rat, we find that c-JUN binds to a subset of injury-induced enhancers. To test the role of specific injury-induced enhancers, we focused on c-JUN-binding enhancers upstream of the Sonic hedgehog (Shh) gene, which is only upregulated in repair Schwann cells compared with other stages of Schwann cell development. We used targeted deletions in male/female mice to show that the enhancers are required for robust induction of the Shh gene after injury.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 6506-6517 |
| Number of pages | 12 |
| Journal | Journal of Neuroscience |
| Volume | 42 |
| Issue number | 34 |
| DOIs | |
| State | Published - Aug 24 2022 |
Funding
This work was supported by the National Institutes of Health–National Institute of Neurological Disorders and Stroke Grant R01 NS100510 to J.S. and, in part, by a core grant (P50 HD105353) to the Waisman Center from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. We thank the University of Wisconsin Biotechnology Center DNA Sequencing Facility for sequencing services and Dr. Lynn Doglio at the Northwestern Transgenic and Targeted Mutagenesis Laboratory for generation of mice. Received Jan. 17, 2022; revised June 17, 2022; accepted June 27, 2022. Author contributions: Z.T., W.-C.X., and L.M. designed research; Z.T., Z.L., Y.L., F.L., and T.W.L. performed research; Z.T. and H.R. analyzed data; Z.T. wrote the first draft of the paper; Z.T., Y.L., and L.M. edited the paper; Z.T. and L.M. wrote the paper. This work was supported by the National Institutes of Health to L.M. and W.-C.X.; and Veterans Affairs to L.M. and W.-C.X. Contact for reagent and resource sharing: Further information and requests for reagents and resources should be directed to and will be fulfilled by corresponding author. The data that support the findings of this study are available from the corresponding author upon reasonable request. Source files are provided. *Z.T. and Z.L. contributed equally to this work. The authors declare no competing financial interests. Correspondence should be addressed to Lin Mei at [email protected]. https://doi.org/10.1523/JNEUROSCI.0131-22.2022 Copyright © 2022 the authors
Keywords
- Schwann
- c-Jun
- enhancer
- injury
- nerve
- transcription
ASJC Scopus subject areas
- General Neuroscience