Zhang Di, Rubio Rodríguez-Kirby Leslie A, Lin Yingxin, Song Mengyi, Wang Li, Wang Lijun, Kanatani Shigeaki, Jimenez-Beristain Tony, Dang Yonglong, Zhong Mei, Kukanja Petra, Wang Shaohui, Chen Xinyi Lisa, Gao Fu, Wang Dejiang, Xu Hang, Lou Xing, Liu Yang, Chen Jinmiao, Sestan Nenad, Uhlén Per, Kriegstein Arnold, Zhao Hongyu, Castelo-Branco Gonçalo, Fan Rong
Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
These authors contributed equally.
bioRxiv. 2024 Jul 28:2024.07.28.605493. doi: 10.1101/2024.07.28.605493.
The ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag-RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains. Specifically, in the cortical area, we discovered temporal persistence and spatial spreading of chromatin accessibility for the layer-defining transcription factors. In corpus callosum, we observed dynamic chromatin priming of myelin genes across the subregions. Together, it suggests a role for layer specific projection neurons to coordinate axonogenesis and myelination. We further mapped the brain of a lysolecithin (LPC) neuroinflammation mouse model and observed common molecular programs in development and neuroinflammation. Microglia, exhibiting both conserved and distinct programs for inflammation and resolution, are transiently activated not only at the core of the LPC lesion, but also at distal locations presumably through neuronal circuitry. Thus, this work unveiled common and differential mechanisms in brain development and neuroinflammation, resulting in a valuable data resource to investigate brain development, function and disease.
在不同时间点对多层组学信息进行空间映射的能力，有助于探索驱动大脑发育、分化、区域化以及疾病中变化的机制。在此，我们开发并应用了空间三重组学测序技术，即DBiT ARP-seq（空间ATAC-RNA-蛋白质测序）和DBiT CTRP-seq（空间CUT&Tag-RNA-蛋白质测序），并结合多重免疫荧光成像（CODEX）来绘制大脑发育和神经炎症中的空间动态重塑图谱。我们在从出生后第0天到第21天的不同阶段获得了小鼠大脑的时空三重组学图谱，并与人类发育中大脑的感兴趣区域进行了比较。具体而言，在皮质区域，我们发现了定义层的转录因子染色质可及性的时间持续性和空间扩散。在胼胝体中，我们观察到髓鞘基因在各亚区域的动态染色质启动。综合起来，这表明层特异性投射神经元在协调轴突发生和髓鞘形成中发挥作用。我们进一步绘制了溶血卵磷脂（LPC）神经炎症小鼠模型的大脑图谱，并观察到发育和神经炎症中的共同分子程序。小胶质细胞在炎症和消退方面表现出保守和独特的程序，不仅在LPC损伤的核心部位短暂激活，而且可能通过神经元回路在远端位置也被激活。因此，这项工作揭示了大脑发育和神经炎症中的共同和差异机制，产生了一个有价值的数据资源，用于研究大脑发育、功能和疾病。
