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

## TL;DR

The study reveals how enhancers control cell-specific responses to CNS injury and enables targeting of reactive astrocytes for potential therapies.

## Contribution

The work decodes how injury-responsive enhancers retain cell-type specificity and can be used to target specific cell states in the CNS.

## Key findings

- Thousands of injury-induced enhancers are identified in glial cells of the mouse spinal cord.
- Injury-responsive enhancers integrate stimulus response elements with cell identity programs.
- These enhancers can be used to selectively target reactive astrocytes in vivo using gene delivery vectors.

## Abstract

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.

Zamboni et al. reveal how enhancers encode cell-type-specific responses to CNS injury. By combining multiomic profiling, deep learning and in vivo screening, they uncover injury-responsive enhancer logic and enable targeting of reactive astrocytes.