A multi-omic atlas of human embryonic skeletal development - Archive ouverte HAL
Article Dans Une Revue Nature Année : 2024

A multi-omic atlas of human embryonic skeletal development

Raphael Blain
Tong Li
Peng He
Xiaoling He
Roger A Barker
Christopher D Buckley
Sarah A Teichmann

Résumé

Human embryonic bone and joint formation is determined by coordinated differentiation of progenitors in the nascent skeleton. The cell states, epigenetic processes and key regulatory factors that underlie lineage commitment of these cells remain elusive. Here we applied paired transcriptional and epigenetic profiling of approximately 336,000 nucleus droplets and spatial transcriptomics to establish a multi-omic atlas of human embryonic joint and cranium development between 5 and 11 weeks after conception. Using combined modelling of transcriptional and epigenetic data, we characterized regionally distinct limb and cranial osteoprogenitor trajectories across the embryonic skeleton and further described regulatory networks that govern intramembranous and endochondral ossification. Spatial localization of cell clusters in our in situ sequencing data using a new tool, ISS-Patcher, revealed mechanisms of progenitor zonation during bone and joint formation. Through trajectory analysis, we predicted potential non-canonical cellular origins for human chondrocytes from Schwann cells. We also introduce SNP2Cell, a tool to link celltype-specific regulatory networks to polygenic traits such as osteoarthritis. Using osteolineage trajectories characterized here, we simulated in silico perturbations of genes that cause monogenic craniosynostosis and implicate potential cell states and disease mechanisms. This work forms a detailed and dynamic regulatory atlas of bone and cartilage maturation and advances our fundamental understanding of cell-fate determination in human skeletal development.
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hal-04863839 , version 1 (04-01-2025)

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Ken To, Lijiang Fei, J. Patrick Pett, Kenny Roberts, Raphael Blain, et al.. A multi-omic atlas of human embryonic skeletal development. Nature, 2024, 635 (8039), pp.657 - 667. ⟨10.1038/s41586-024-08189-z⟩. ⟨hal-04863839⟩
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