Introduction
In the field of life sciences, exploring how cells undergo the entire lifecycle from birth to maturity and then to aging is crucial for understanding the development of organisms, maintaining homeostasis, and the progression of diseases. In recent years, with the advancement of single-cell sequencing technologies, scientists have been able to observe the heterogeneity and complexity of cells at an unprecedented resolution. However, accurately inferring the developmental trajectory and “age” of cells at the single-cell level remains a challenge. In this context, an innovative study published on May 9 in Nature Biotechnology titled “Tracking single-cell evolution using clock-like chromatin accessibility loci” provides us with a new perspective and tool.
This study developed a method called EpiTrace, which can track the “mitotic age” of cells in a clock-like manner using single-cell chromatin accessibility sequencing (scATAC-seq) data. This discovery not only provides new molecular markers for understanding the lifecycle of cells but also offers new strategies for studying complex biological processes such as cell fate determination, tissue regeneration, aging, and tumorigenesis. The key to EpiTrace technology lies in identifying and utilizing specific regions in the genome known as “clock-like differential methylation loci” (ClockDML). The DNA methylation (DNAm) patterns of these regions change with cell division, reflecting the age of the cells. Researchers found that as cells divide, the heterogeneity of chromatin accessibility (ClockAcc) in these regions decreases, providing a new metric for measuring the mitotic age of cells.
With EpiTrace technology, researchers can estimate cell age and lineage tracing across various cell types and species. This method not only aligns with known developmental hierarchies but also correlates well with DNAm-based clocks and can complement methods based on mutation lineage tracing, RNA velocity, and stemness predictions. Furthermore, EpiTrace technology also reveals that during the process of cell reprogramming, the epigenetic age of cells can be reset, which has significant implications for regenerative medicine and cell therapy. In the field of oncology, the application of EpiTrace technology also shows great potential. By analyzing glioblastoma (GBM) samples, researchers were able to trace the evolutionary process of tumor clones, revealing early heterogeneity of tumor cells and the evolutionary trajectories of clone branches. This provides new clues for understanding tumor heterogeneity and treatment resistance.
Overall, the emergence of EpiTrace technology not only provides a new research tool for the field of cell biology but also opens new avenues for clinically relevant biomedical research. As the technology continues to be optimized and improved, we hope to uncover more mysteries about cellular aging and disease development in the future, providing new strategies for the diagnosis and treatment of related diseases.
In the field of life sciences, understanding how cells evolve over time is a core issue. The method developed in this study, named EpiTrace, can track the “age” and lineage development of cells through single-cell chromatin accessibility sequencing (scATAC-seq) data. The emergence of this technology not only provides us with new tools to understand the lifecycle of cells but also opens new pathways for clinically relevant biomedical research.The “Clock” of Cells: Chromatin Accessibility and Cell AgeThe age of a cell, or “mitotic age,” refers to the number of divisions a cell has undergone. Traditionally, researchers estimated the mitotic age of cells by observing telomere length, but this method has limitations. The innovation of EpiTrace technology lies in its utilization of changes in chromatin accessibility to measure cell age. Chromatin accessibility refers to the degree to which certain regions of the genome are accessible to proteins such as transcription factors, which is closely related to gene expression regulation. Researchers found that as cells divide, the DNA methylation (DNAm) patterns of specific genomic regions (referred to as ClockDML) change, and this change is associated with the age of the cells. The heterogeneity of chromatin accessibility (ClockAcc) in these regions decreases during cell division, providing a new metric for measuring the mitotic age of cells.EpiTrace Technology: From Theory to ApplicationEpiTrace technology determines cell age and performs lineage tracing by calculating the proportion of open ClockDML sites in scATAC-seq data. This method not only aligns with known developmental hierarchies but also correlates well with DNAm-based clocks and can complement methods based on mutation lineage tracing, RNA velocity, and stemness predictions. By applying EpiTrace technology, researchers can estimate cell age and perform lineage tracing across various cell lineages and animal species. This provides new biological insights for studying hematopoiesis, organ development, tumor biology, and immunology, and has potential clinical applications.Cross-Species Prediction of Cell AgeAnother remarkable feature of EpiTrace technology is its universality. Researchers found that even in species without active DNA methylation, such as Drosophila melanogaster, EpiTrace can predict cell age by identifying genomic regions homologous to human ClockDML. This suggests that similar chromatin accessibility patterns may be conserved across species, providing new avenues for studying cellular aging in different organisms.Cell Fate and the Epigenetic ClockEpiTrace technology also reveals that during the process of cell reprogramming, such as the generation of induced pluripotent stem cells (iPSCs), the epigenetic age of cells can be reset. This means that through specific chemical induction, adult cells can revert to a state similar to that of early embryonic cells, a finding that has significant implications for regenerative medicine and cell therapy.Recovering Cell Development Trajectories from Static SnapshotsAdditionally, EpiTrace technology can infer epigenetic changes during cell development from single-cell chromatin accessibility data of adult tissues. For example, in studies of kidney cells, EpiTrace technology revealed the birth order of kidney cells and associated it with their spatial positions in the kidney. This provides new perspectives for understanding kidney development and disease.Tracking Tumor Clone EvolutionIn the field of oncology, the application of EpiTrace technology also shows great potential. By analyzing glioblastoma (GBM) samples, researchers were able to trace the evolutionary process of tumor clones, revealing early heterogeneity of tumor cells and the evolutionary trajectories of clone branches.The advent of EpiTrace technology provides us with a new tool to study the lifecycle and lineage development of cells with unprecedented precision and resolution. The application prospects of this technology are vast, whether in basic biological research or in clinical treatment and drug development, it holds great potential. As the technology continues to be optimized and improved, we hope to uncover more mysteries about cellular aging and disease development in the future.Original Link
Xiao Y, Jin W, Ju L, Fu J, Wang G, Yu M, Chen F, Qian K, Wang X, Zhang Y. Tracking single-cell evolution using clock-like chromatin accessibility loci. Nat Biotechnol. 2024 May 9. doi: 10.1038/s41587-024-02241-z. Epub ahead of print. PMID: 38724668.
https://www.nature.com/articles/s41587-024-02241-z
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