The regulatory code of injury-responsive enhancers enables precision cell-state targeting in the CNS.

Zamboni M, Martínez-Martín A, Rydholm G, Häneke T, Pintado Almeida L, Seçilmiş D, Ziegenhain C, Llorens-Bobadilla E

Nat. Neurosci. 29 (2) 337-349 [2026-02-00; online 2025-12-02]

Enhancer elements direct cell-type-specific gene expression programs. After injury, cells change their transcriptional state to adapt to stress and initiate repair. Here we investigate how injury-induced transcriptional programs are encoded within enhancers in the mammalian CNS. Leveraging single-nucleus transcriptomics and chromatin accessibility profiling, we identify thousands of injury-induced, cell-type-specific enhancers in the mouse spinal cord after a contusion injury. These are abundant in glial cells and retain cell-type specificity, even when regulating shared wound response genes. By modeling glial injury-responsive enhancers using deep learning, we reveal that their architecture encodes cell-type specificity by integrating generic stimulus response elements with cell identity programs. Finally, through in vivo enhancer screening, we demonstrate that injury-responsive enhancers can selectively target reactive astrocytes across the CNS using therapeutically relevant gene delivery vectors. Our decoding of the principles of injury-responsive enhancers enables the design of sequences that can be programmed to target disease-associated cell states.

PubMed 41331142

DOI 10.1038/s41593-025-02131-w

Crossref 10.1038/s41593-025-02131-w

pmc: PMC12880913
pii: 10.1038/s41593-025-02131-w