Three-dimensional chromatin mapping of sensory neurons reveals that promoter–enhancer looping is required for axonal regeneration
The in vivo three-dimensional genomic architecture of adult mature neurons at homeostasis and after medically relevant perturbations such as axonal injury remains elusive. Here, we address this knowledge gap by mapping the three-dimensional chromatin architecture and gene expression program at homeostasis and after sciatic nerve injury in wild-type and cohesin-deficient mouse sensory dorsal root ganglia neurons via combinatorial Hi-C, promoter-capture Hi-C, CUT&Tag for H3K27ac and RNA-seq. We find that genes involved in axonal regeneration form long-range, complex chromatin loops, and that cohesin is required for the full induction of the regenerative transcriptional program. Importantly, loss of cohesin results in disruption of chromatin architecture and severely impaired nerve regeneration. Complex enhancer-promoter loops are also enriched in the human fetal cortical plate, where the axonal growth potential is highest, and are lost in mature adult neurons. Together, these data provide an original three-dimensional chromatin map of adult sensory neurons in vivo and demonstrate a role for cohesin-dependent long-range promoter interactions in nerve regeneration.
Authors
- Francesco De Virgiliis (ORCID: https://orcid.org/0000-0001-7170-1013)
- Guiping Kong (ORCID: https://orcid.org/0000-0001-7662-6948)
- Sree Gongala
- Bryce Collison
- Franziska Mueller (ORCID: https://orcid.org/0000-0003-2070-7508)
- Ediem Al-Jibury (ORCID: https://orcid.org/0000-0003-2466-0989)
- Jessica Chadwick (ORCID: https://orcid.org/0000-0001-7287-7707)
- Eleonora De Vitis (ORCID: https://orcid.org/0009-0004-0061-7040)
- Matthias Merkenschlager (ORCID: https://orcid.org/0000-0003-2889-3288)
- Yuyang Yan (ORCID: https://orcid.org/0000-0002-2538-9046)
- Ilaria Palmisano (ORCID: https://orcid.org/0000-0002-7139-8090)
- Alessandro Carlino (ORCID: https://orcid.org/0000-0003-1868-7317)
- Luming Zhou (ORCID: https://orcid.org/0000-0002-7284-1744)
- Simone Di Giovanni (ORCID: https://orcid.org/0000-0003-3154-5399)
- James W. D. King (ORCID: https://orcid.org/0009-0009-7847-6475)
- Rebecca Toscano Rivalta
- Zheng Wang (ORCID: https://orcid.org/0000-0002-8388-6139)
- Tong Liu
- Wei Gao (ORCID: https://orcid.org/0009-0008-3761-888X)
Institutions
- University of Miami (US)
- MRC London Institute of Medical Sciences (GB)
- Imperial College London (GB)
- The Ohio State University (US)
- Medical Research Council (GB)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-09-10
- DOI
- https://doi.org/10.1073/pnas.2402518121
- Citations
- 11
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 2.57
Funders
- Ohio State University
- National Institute for Health and Care Research
- Imperial College London
- Rosetrees Trust
- National Institutes of Health
- Medical Research Council
- NIHR Imperial Biomedical Research Centre
- National Institute of General Medical Sciences