瑞典卡罗林斯卡学院Enric Llorens-Bobadilla小组近日取得一项新成果。经过不懈努力，他们发现了损伤反应增强子的调控代码能够在中枢神经系统中实现精确的细胞状态靶向。2025年12月2日，国际知名学术期刊《自然—神经科学》发表了这一成果。

在这里，该研究组研究了损伤诱导的转录程序是如何在哺乳动物中枢神经系统的增强子中编码的。利用单核转录组学和染色质可及性分析，该课题组确定了损伤后无主题脊髓中损伤诱导的细胞类型特异性增强子的需求。这些蛋白在神经胶质细胞中丰富，即使在调节共同的伤口反应基因时也能保持细胞类型特异性。通过模拟以深度学习为主题的神经胶质损伤反应增强子，课题组揭示了它们的结构通过将通用刺激反应元件与细胞身份程序集成来编码细胞类型特异性。

最后，通过体内增强子筛选，该课题组人员证明了损伤反应性增强子可以选择性地靶向中枢神经系统中反应性星形胶质细胞，以治疗相关的基因传递载体为主题。他们破译了损伤反应增强子的原理，从而能够设计出针对疾病相关细胞状态的序列。

据介绍，增强子元件直接细胞类型特异性基因表达程序。损伤后，细胞改变其转录状态以适应应激并启动修复。

附：英文原文

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

Author: Zamboni, Margherita, Martnez-Martn, Adrin, Rydholm, Gabriel, Hneke, Timm, Pintado Almeida, Laura, Seilmi, Deniz, Ziegenhain, Christoph, Llorens-Bobadilla, Enric

Issue&Volume: 2025-12-02

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.

DOI: 10.1038/s41593-025-02131-w

Source: https://www.nature.com/articles/s41593-025-02131-w