03138nas a2200613   4500000000100000000000100001008004100002260001200043653002100055653001900076100001100095700001600106700002000122700001800142700001800160700002300178700001200201700001600213700001200229700001300241700001800254700001600272700001400288700002200302700001300324700001800337700002100355700001800376700001700394700001900411700002300430700001700453700001400470700001800484700002500502700001900527700001700546700001700563700001600580700001600596700002100612700002100633700002000654700001900674700002000693700002700713700002300740245006300763856005500826300001200881490000800893520160900901022001402510       2024                            d  c2024-1110aBone development10aRNA sequencing1 aKen To1 aLijiang Fei1 aJ. Patrick Pett1 aKenny Roberts1 aRaphael Blain1 aKrzysztof Polanski1 aTong Li1 aNadav Yayon1 aPeng He1 aChuan Xu1 aJames Cranley1 aMadelyn Moy1 aRuoyan Li1 aKazumasa Kanemaru1 aNi Huang1 aStathis Megas1 aLaura Richardson1 aRakesh Kapuge1 aShani Perera1 aElizabeth Tuck1 aAnna Wilbrey-Clark1 aIlaria Mulas1 aFani Memi1 aBatuhan Cakir1 aAlexander V. Predeus1 aDavid Horsfall1 aSimon Murray1 aMartin Prete1 aPavel Mazin1 aXiaoling He1 aKerstin B. Meyer1 aMuzlifah Haniffa1 aRoger A. Barker1 aOmer Bayraktar1 aAlain Chédotal1 aChristopher D. Buckley1 aSarah A. Teichmann00aA multi-omic atlas of human embryonic skeletal development  uhttps://www.nature.com/articles/s41586-024-08189-z  a657-6670 v6353 aHuman 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.  a1476-4687