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Lookup NU author(s): Professor Muzlifah Haniffa
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.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.
Author(s): To K, Fei L, Pett JP, Roberts K, Blain R, Polanski K, Li T, Yayon N, He P, Xu C, Cranley J, Moy M, Li R, Kanemaru K, Huang N, Megas S, Richardson L, Kapuge R, Perera S, Tuck E, Wilbrey-Clark A, Mulas I, Memi F, Cakir B, Predeus AV, Horsfall D, Murray S, Prete M, Mazin P, He X, Meyer KB, Haniffa M, Barker RA, Bayraktar O, Chedotal A, Buckley CD, Teichmann SA
Publication type: Article
Publication status: Published
Journal: Nature
Year: 2024
Volume: 635
Issue: 8039
Pages: 657-667
Print publication date: 21/11/2024
Online publication date: 20/11/2024
Acceptance date: 09/10/2024
Date deposited: 02/12/2024
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Nature Research
URL: https://doi.org/10.1038/s41586-024-08189-z
DOI: 10.1038/s41586-024-08189-z
Data Access Statement: High-throughput raw sequencing data in this study are available from ArrayExpress (www.ebi.ac.uk/arrayexpress) with the accession number E-MTAB-14385. Processed snRNA–scATAC-seq, Visium and ISS data are available for visualization and can be downloaded from https://developmental.cellatlas.io/skeleton-development. Source data are provided with this paper. ISS-Patcher is available at https://github.com/Teichlab/iss_patcher. SNP2Cell is available at https://github.com/Teichlab/snp2cell. The custom code for the other analyses performed in this study is available at GitHub (https://github.com/Teichlab/skeletal_dev_atlas).
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