Temporal recording of mammalian development and precancer

Mirazul Islam, Yilin Yang, Alan J. Simmons, Vishal M. Shah, Krushna Pavan Musale, Yanwen Xu, Naila Tasneem, Zhengyi Chen, Linh T. Trinh, Paola Molina, Marisol A. Ramirez-Solano, Iannish D. Sadien, Jinzhuang Dou, Andrea Rolong, Ken Chen, Mark A. Magnuson, Jeffrey C. Rathmell, Ian G. Macara, Douglas J. Winton, Qi Liu, Hamim Zafar, Reza Kalhor, George M. Church, Martha J. Shrubsole, Robert J. Coffey () and Ken S. Lau ()
Additional contact information
Mirazul Islam: Vanderbilt University Medical Center
Yilin Yang: Vanderbilt University Medical Center
Alan J. Simmons: Vanderbilt University Medical Center
Vishal M. Shah: Vanderbilt University Medical Center
Krushna Pavan Musale: Indian Institute of Technology Kanpur
Yanwen Xu: Vanderbilt University Medical Center
Naila Tasneem: Vanderbilt University Medical Center
Zhengyi Chen: Vanderbilt University Medical Center
Linh T. Trinh: Vanderbilt University
Paola Molina: Vanderbilt University
Marisol A. Ramirez-Solano: Vanderbilt University Medical Center
Iannish D. Sadien: University of Cambridge
Jinzhuang Dou: The University of Texas MD Anderson Cancer Center
Andrea Rolong: Vanderbilt University Medical Center
Ken Chen: The University of Texas MD Anderson Cancer Center
Mark A. Magnuson: Vanderbilt University
Jeffrey C. Rathmell: Vanderbilt University Medical Center
Ian G. Macara: Vanderbilt University Medical Center
Douglas J. Winton: University of Cambridge
Qi Liu: Vanderbilt University Medical Center
Hamim Zafar: Indian Institute of Technology Kanpur
Reza Kalhor: Johns Hopkins University School of Medicine
George M. Church: Harvard Medical School
Martha J. Shrubsole: Vanderbilt University Medical Center
Robert J. Coffey: Vanderbilt University Medical Center
Ken S. Lau: Vanderbilt University Medical Center

Nature, 2024, vol. 634, issue 8036, 1187-1195

Abstract: 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 ordering3–5. 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 418 human 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.

Date: 2024
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DOI: 10.1038/s41586-024-07954-4

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