美国范德比尔特大学医学中心Ken S. Lau和Robert J. Coffey共同合作，近期取得重要工作进展。他们研究提出了哺乳动物发育和癌前病变的时间记录方法。相关研究成果相关论文于2024年10月30日在线发表于《自然》杂志上。

据介绍，细胞事件的时间顺序提供了对生物现象的基本见解。虽然传统上通过持续的直接观察来实现，但另一种方法是利用不可逆的遗传变化（如自然发生的突变）来创造不可磨灭的标记，从而实现回顾性时间排序。

使用一种多功能的单细胞CRISPR平台，研究人员开发了一种分子时钟方法，可以记录细胞事件的时间和体内的克隆性，同时整合细胞状态和谱系信息。

通过这种方法，研究人员揭示了小鼠胚胎发育过程中，组织特异性细胞扩展的精确时间和细胞类型之间的非传统发育关系，以及基于其独特遗传历史的新上皮祖细胞状态。

对小鼠腺瘤的分析，结合人类癌前病变的多组学和单细胞分析，并通过对418个人类息肉的克隆分析，显示在15-30%的结肠癌前病变中发生了多克隆起始，表明它们起源于多个正常的起始细胞。

总之，这一研究提出了一个多模式框架，为体内记录奠定了基础，通过将合成或自然的不可磨灭的遗传变化与单细胞分析相结合，以探索哺乳动物系统中发育和肿瘤发生的起源与时间。

附：英文原文

Title: Temporal recording of mammalian development and precancer

Author: Islam, Mirazul, Yang, Yilin, Simmons, Alan J., Shah, Vishal M., Musale, Krushna Pavan, Xu, Yanwen, Tasneem, Naila, Chen, Zhengyi, Trinh, Linh T., Molina, Paola, Ramirez-Solano, Marisol A., Sadien, Iannish D., Dou, Jinzhuang, Rolong, Andrea, Chen, Ken, Magnuson, Mark A., Rathmell, Jeffrey C., Macara, Ian G., Winton, Douglas J., Liu, Qi, Zafar, Hamim, Kalhor, Reza, Church, George M., Shrubsole, Martha J., Coffey, Robert J., Lau, Ken S.

Issue&Volume: 2024-10-30

Abstract: Temporal ordering of cellular events offers fundamental insights into biological phenomena. Although this is traditionally achieved through continuous direct observations1,2, an alternative solution leverages irreversible genetic changes, such as naturally occurring mutations, to create indelible marks that enables retrospective temporal ordering3,4,5. Using a multipurpose, single-cell CRISPR platform, we developed a molecular clock approach to record the timing of cellular events and clonality in vivo, with incorporation of cell state and lineage information. Using this approach, we uncovered precise timing of tissue-specific cell expansion during mouse embryonic development, unconventional developmental relationships between cell types and new epithelial progenitor states by their unique genetic histories. Analysis of mouse adenomas, coupled to multiomic and single-cell profiling of human precancers, with clonal analysis of 418human polyps, demonstrated the occurrence of polyclonal initiation in 15–30% of colonic precancers, showing their origins from multiple normal founders. Our study presents a multimodal framework that lays the foundation for in vivo recording, integrating synthetic or natural indelible genetic changes with single-cell analyses, to explore the origins and timing of development and tumorigenesis in mammalian systems.

DOI: 10.1038/s41586-024-07954-4

Source: https://www.nature.com/articles/s41586-024-07954-4