Department of Medicine, Division of Brain Sciences, Centre for Restorative Neuroscience, Imperial College London, London W12 0NN, United Kingdom.
Department of Neuroscience, Department of Plastic and Reconstructive Surgery, The Ohio State University, Columbus, OH 43210.
Proc Natl Acad Sci U S A. 2024 Sep 17;121(38):e2402518121. doi: 10.1073/pnas.2402518121. Epub 2024 Sep 10.
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.
在体内，成熟神经元在稳态和医学相关扰动（如轴突损伤）后的三维基因组结构仍然难以捉摸。在这里，我们通过组合 Hi-C、启动子捕获 Hi-C、用于 H3K27ac 的 CUT&Tag 和 RNA-seq，在野生型和黏连蛋白缺陷型小鼠感觉背根神经节神经元中，在稳态和坐骨神经损伤后绘制三维染色质结构和基因表达程序，解决了这一知识空白。我们发现，参与轴突再生的基因形成长程、复杂的染色质环，黏连蛋白对于完全诱导再生转录程序是必需的。重要的是，黏连蛋白的缺失导致染色质结构的破坏和神经再生的严重受损。复杂的增强子-启动子环在人类胎儿皮质板中也很丰富，而皮质板的轴突生长潜力最高，在成熟的成年神经元中丢失。总之，这些数据提供了体内成熟感觉神经元的原始三维染色质图谱，并证明了黏连蛋白依赖性长程启动子相互作用在神经再生中的作用。
