Research Article

Lineage tracing on transcriptional landscapes links state to fate during differentiation

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Science  23 Jan 2020:
eaaw3381
DOI: 10.1126/science.aaw3381

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Abstract

A challenge in biology is to associate molecular differences among progenitor cells with their capacity to generate mature cell types. Here, we use expressed DNA barcodes to clonally trace transcriptomes over time and applied this to study fate determination in hematopoiesis. We identify states of primed fate potential and locate them on a continuous transcriptional landscape. We identify two routes of monocyte differentiation that leave an imprint on mature cells. Yet analysis of sister cells also reveals cells to have intrinsic fate biases not detectable by single-cell RNA sequencing. Finally, we benchmark computational methods of dynamic inference from single-cell snapshots, showing that fate choice occurs earlier than is detected by state-of the-art algorithms, and that cells progress steadily through pseudotime with precise and consistent dynamics.

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