Amazing stuff!
I am not sure I like the expression "DNA typewriter". Obviously, a bad choice! When was the last time any of the involved researchers used a typewriter if ever?
"Decades ago, biologists traced the history of the thousand or so cells that create a nematode from single, fertilized cell.
Documenting such a developmental map for a mammalian embryo is much, much harder for various reasons. Two teams, however, have used genome editing tools in mouse embryonic stem cells or mouse zygotes to create the most comprehensive cell lineage maps so far for early mammalian development.
As the cells of a mouse embryo divided, the editors inserted DNA sequences that let researchers later discern their lineages. Revealed in parallel papers in Cell and Science , the studies chart cell relationships up to the point where the embryonic rodents’ organs begin to form. “ ...
The ultimate goal, a family tree tracing the ancestry of every cell in the mammalian body, could clarify how organs arise, probe the origins of birth defects, help grow better replacement cells for patients, and improve evolutionary studies."
"... To generate lineage maps for mice, both research teams used a DNA-modifying technique known as prime editing to insert distinctive marker sequences into the genomes of embryonic cell as development proceeded. From the modifications that descendant cells accumulated, the researchers could reconstruct how they were related. ..."
From the highlights and abstract (1):
"Highlights
• PEtracer resolves fate dynamics throughout early mouse embryogenesis
• >1.4 million deeply sequenced cells with ∼75% of cell divisions marked
• Quantitative view of lineage biases, restriction timing, and clonal outputs by tissue
• Highly reproducible lineage architecture across independent replicate embryos
Summary
A comprehensive cell fate map of mammalian embryogenesis has remained out of reach given the scale, cellular diversity, and non-deterministic nature of development in utero.
Here, we use PEtracer to continuously install heritable genetic marks as development progresses, reconstructing lineage trees that resolve ∼75% of cell divisions across >1.4 million cells from 16 replicate embryos.
We pair these trees with deep transcriptional profiling to resolve cell fate biases, restriction timing, progenitor pool sizes, and lineage relationships throughout embryogenesis.
Using this quantitative reference, we uncover strikingly reproducible lineage architecture between replicate embryos and chart the lineage dynamics driving fate specification across diverse tissues.
Specific biological insights include the progressive restriction of neural crest fate, the relative contributions of distinct mesodermal origins to endothelium, and the dynamics of axial elongation. This work provides a foundation for a quantitative and predictive understanding of mammalian development."
From the abstract (2):
"Mammalian biology unfolds over time, within tissues and organs opaque to our eyes and instruments.
We applied DNA Typewriter, a sequential molecular recorder, to record the cell lineage of a mouse over nearly two weeks of development.
From one embryo, we reconstruct a time-calibrated, parsimony-supported, zygote-rooted phylogeny of 1.28 million transcriptionally profiled cells.
A burst of editing unequivocally marks the daughters of the first cleavage, which serve as inline replicates.
We quantify clonal dominance arising during gastrulation.
Tree siblings share cell type far above chance; heterotypic siblings mark terminal differentiations. Temporal sweeps of clade co-occurrence recover a dated hierarchy of cell-type couplings; imputed labels for internal nodes recapitulate known state paths. A lineage-anchored ontogeny of mammalian development, long out of reach, is coming into view."
Comprehensive lineage tracing maps the landscape of cell fate decisions in mouse embryogenesis (1, open access)
A DNA Typewriter records the cell lineage history of a mouse, from zygote to late organogenesis (2, no public access)
A DNA Typewriter records the cell lineage history of a mouse, from zygote to late organogenesis (2, preprint, open access)
Graphical abstract (1)
Figure 1 Embryonic-scale cell fate mapping of mouse development with PEtracer (1)
Figure 1. Pronuclear zygotic injection (PNI) of DNA Typewriter components identifies an E13.5 embryo with robust levels of sequential editing. (2)
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