TY - JOUR
KW - Bone development
KW - RNA sequencing
AU - Ken To
AU - Lijiang Fei
AU - J. Patrick Pett
AU - Kenny Roberts
AU - Raphael Blain
AU - Krzysztof Polanski
AU - Tong Li
AU - Nadav Yayon
AU - Peng He
AU - Chuan Xu
AU - James Cranley
AU - Madelyn Moy
AU - Ruoyan Li
AU - Kazumasa Kanemaru
AU - Ni Huang
AU - Stathis Megas
AU - Laura Richardson
AU - Rakesh Kapuge
AU - Shani Perera
AU - Elizabeth Tuck
AU - Anna Wilbrey-Clark
AU - Ilaria Mulas
AU - Fani Memi
AU - Batuhan Cakir
AU - Alexander V. Predeus
AU - David Horsfall
AU - Simon Murray
AU - Martin Prete
AU - Pavel Mazin
AU - Xiaoling He
AU - Kerstin B. Meyer
AU - Muzlifah Haniffa
AU - Roger A. Barker
AU - Omer Bayraktar
AU - Alain Chédotal
AU - Christopher D. Buckley
AU - Sarah A. Teichmann
AB - 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.
BT - Nature
DA - 2024-11
DO - 10.1038/s41586-024-08189-z
IS - 8039
LA - en
N2 - 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.
PY - 2024
SP - 657
EP - 667
T2 - Nature
TI - A multi-omic atlas of human embryonic skeletal development
UR - https://www.nature.com/articles/s41586-024-08189-z
VL - 635
Y2 - 2024-11-26
SN - 1476-4687
ER -