Faculty, Staff and Student Publications
Publication Date
10-1-2024
Journal
Nature
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.
Keywords
Animals, Female, Humans, Male, Mice, Adenoma, Carcinogenesis, Cell Lineage, Clone Cells, Colonic Neoplasms, CRISPR-Cas Systems, Embryonic Development, Organ Specificity, Precancerous Conditions, Single-Cell Analysis, Time Factors, Multiomics, Polyps, Cancer genetics, Evolution, Biotechnology, Organogenesis, Colorectal cancer
DOI
10.1038/s41586-024-07954-4
PMID
39478207
PMCID
PMC11525190
PubMedCentral® Posted Date
10-30-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons
