A multi-omic atlas of human embryonic skeletal development

被引：6

作者：

Ken To ^{[1
]}

Lijiang Fei ^{[2
]}

J. Patrick Pett ^{[1
]}

Kenny Roberts ^{[1
]}

Raphael Blain ^{[1
]}

Krzysztof Polański ^{[3
]}

Tong Li ^{[1
]}

Nadav Yayon ^{[1
]}

Peng He ^{[1
]}

Chuan Xu ^{[4
]}

James Cranley ^{[1
]}

Madelyn Moy ^{[4
]}

Ruoyan Li ^{[5
]}

Kazumasa Kanemaru ^{[1
]}

Ni Huang ^{[1
]}

Stathis Megas ^{[6
]}

Laura Richardson ^{[1
]}

Rakesh Kapuge ^{[1
]}

Shani Perera ^{[1
]}

Elizabeth Tuck ^{[1
]}

Anna Wilbrey-Clark ^{[1
]}

Ilaria Mulas ^{[7
]}

Fani Memi ^{[1
]}

Batuhan Cakir ^{[1
]}

Alexander V. Predeus ^{[1
]}

David Horsfall ^{[1
]}

Simon Murray ^{[1
]}

Martin Prete ^{[1
]}

Pavel Mazin ^{[1
]}

Xiaoling He ^{[1
]}

Kerstin B. Meyer ^{[1
]}

Muzlifah Haniffa ^{[1
]}

Roger A. Barker ^{[1
]}

Omer Bayraktar ^{[1
]}

Alain Chédotal ^{[1
]}

Christopher D. Buckley ^{[8
]}

Sarah A. Teichmann ^{[9
]}

机构：

[1] Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton

[2] Department of Surgery, University of Cambridge, Cambridge

[3] Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris

[4] European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge

[5] Department of Pathology, University of California, San Francisco, San Francisco, CA

[6] Department of Medicine, University of Cambridge, Cambridge

[7] Cambridge Centre for AI in Medicine, Department of Applied Mathematics and Theoretical Physics, Cambridge

[8] John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge

[9] Cambridge Stem Cell Institute, University of Cambridge, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge

[10] Newcastle University, Biosciences Institute, Newcastle University, Newcastle upon Tyne

[11] Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne

[12] Institut de Pathologie, Groupe Hospitalier Est, Hospices Civils de Lyon, Lyon

[13] University Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, Lyon

[14] Kennedy Institute of Rheumatology, University of Oxford, Oxford

[15] CIFAR Macmillan Multi-scale Human Programme, CIFAR, Toronto

来源：

Nature | 2024年 / 635卷 / 8039期

基金：

英国科研创新办公室; 欧盟地平线“2020”; 英国惠康基金; 英国医学研究理事会;

关键词：

D O I：

10.1038/s41586-024-08189-z

中图分类号：

学科分类号：

摘要：

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. © The Author(s) 2024.

引用

页码：657 / 667

页数：10

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