A multi-omic atlas of human embryonic skeletal development

Ken To, Lijiang Fei, J. Patrick Pett, Kenny Roberts, Raphael Blain, Krzysztof Polański, Tong Li, Nadav Yayon, Peng He, Chuan Xu, James Cranley, Madelyn Moy, Ruoyan Li, Kazumasa Kanemaru, Ni Huang, Stathis Megas, Laura Richardson, Rakesh Kapuge, Shani Perera, Elizabeth Tuck, Anna Wilbrey-Clark, Ilaria Mulas, Fani Memi, Batuhan Cakir, Alexander V. Predeus, David Horsfall, Simon Murray, Martin Prete, Pavel Mazin, Xiaoling He, Kerstin B. Meyer, Muzlifah Haniffa, Roger A. Barker, Omer Bayraktar, Alain Chédotal, Christopher D. Buckley and Sarah A. Teichmann ()
Additional contact information
Ken To: Wellcome Genome Campus
Lijiang Fei: Wellcome Genome Campus
J. Patrick Pett: Wellcome Genome Campus
Kenny Roberts: Wellcome Genome Campus
Raphael Blain: Institut de la Vision
Krzysztof Polański: Wellcome Genome Campus
Tong Li: Wellcome Genome Campus
Nadav Yayon: Wellcome Genome Campus
Peng He: Wellcome Genome Campus
Chuan Xu: Wellcome Genome Campus
James Cranley: Wellcome Genome Campus
Madelyn Moy: Wellcome Genome Campus
Ruoyan Li: Wellcome Genome Campus
Kazumasa Kanemaru: Wellcome Genome Campus
Ni Huang: Wellcome Genome Campus
Stathis Megas: Wellcome Genome Campus
Laura Richardson: Wellcome Genome Campus
Rakesh Kapuge: Wellcome Genome Campus
Shani Perera: Wellcome Genome Campus
Elizabeth Tuck: Wellcome Genome Campus
Anna Wilbrey-Clark: Wellcome Genome Campus
Ilaria Mulas: Wellcome Genome Campus
Fani Memi: Wellcome Genome Campus
Batuhan Cakir: Wellcome Genome Campus
Alexander V. Predeus: Wellcome Genome Campus
David Horsfall: Wellcome Genome Campus
Simon Murray: Wellcome Genome Campus
Martin Prete: Wellcome Genome Campus
Pavel Mazin: Wellcome Genome Campus
Xiaoling He: University of Cambridge
Kerstin B. Meyer: Wellcome Genome Campus
Muzlifah Haniffa: Wellcome Genome Campus
Roger A. Barker: University of Cambridge
Omer Bayraktar: Wellcome Genome Campus
Alain Chédotal: Institut de la Vision
Christopher D. Buckley: University of Oxford
Sarah A. Teichmann: Wellcome Genome Campus

Nature, 2024, vol. 635, issue 8039, 657-667

Abstract: Abstract 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 cell-type-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.

Date: 2024
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DOI: 10.1038/s41586-024-08189-z

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