{"id":["DOI:10.1038/s41586-024-08189-z"],"title":["A multi-omic atlas of human embryonic skeletal development"],"publication_date":["2024-11-20"],"authors":{"AUTHTEMP:00059":{"id":["AUTHTEMP:00059"],"family_name":["To"],"personal_name":["Ken"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]},"ROR:013meh722":{"organization_name":["University of Cambridge"]}}},"ORCID:0000-0002-2066-7297":{"id":["ORCID:0000-0002-2066-7297"],"family_name":["Fei"],"personal_name":["Lijiang"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}},"ORCID:0000-0002-5249-444X":{"id":["ORCID:0000-0002-5249-444X"],"family_name":["Pett"],"personal_name":["J. Patrick"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}},"ORCID:0000-0001-6155-0821":{"id":["ORCID:0000-0001-6155-0821"],"family_name":["Roberts"],"personal_name":["Kenny"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}},"ORCID:0000-0002-8552-0229":{"id":["ORCID:0000-0002-8552-0229"],"family_name":["Blain"],"personal_name":["Raphael"],"affiliations":{"ROR:000zhpw23":{"organization_name":["Institut de la Vision"]}}},"ORCID:0000-0002-2586-9576":{"id":["ORCID:0000-0002-2586-9576"],"family_name":["Polański"],"personal_name":["Krzysztof"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}},"ORCID:0000-0002-8240-4476":{"id":["ORCID:0000-0002-8240-4476"],"family_name":["Li"],"personal_name":["Tong"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger 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Institute"]}}},"ORCID:0000-0002-2750-1599":{"id":["ORCID:0000-0002-2750-1599"],"family_name":["Predeus"],"personal_name":["Alexander V."],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}},"ORCID:0000-0002-8086-812X":{"id":["ORCID:0000-0002-8086-812X"],"family_name":["Horsfall"],"personal_name":["Dave"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]},"ROR:01kj2bm70":{"organization_name":["Newcastle University"]}}},"ORCID:0009-0007-0787-1051":{"id":["ORCID:0009-0007-0787-1051"],"family_name":["Murray"],"personal_name":["Simon"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}},"ORCID:0000-0002-5946-821X":{"id":["ORCID:0000-0002-5946-821X"],"family_name":["Prete"],"personal_name":["Martin"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}},"ORCID:0000-0001-9268-3352":{"id":["ORCID:0000-0001-9268-3352"],"family_name":["Mazin"],"personal_name":["Pavel"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}},"ORCID:0009-0004-1002-8418":{"id":["ORCID:0009-0004-1002-8418"],"family_name":["He"],"personal_name":["Xiaoling"],"affiliations":{"ROR:013meh722":{"organization_name":["University of Cambridge"]},"ROR:05nz0zp31":{"organization_name":["Wellcome/MRC Cambridge Stem Cell Institute"]}}},"ORCID:0000-0001-5906-1498":{"id":["ORCID:0000-0001-5906-1498"],"family_name":["Meyer"],"personal_name":["Kerstin B."],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}},"ORCID:0000-0002-3927-2084":{"id":["ORCID:0000-0002-3927-2084"],"family_name":["Haniffa"],"personal_name":["Muzlifah"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]},"ROR:01kj2bm70":{"organization_name":["Newcastle University"]},"ROR:05p40t847":{"organization_name":["Newcastle upon Tyne Hospitals NHS Foundation Trust"]},"ROR:0187kwz08":{"organization_name":["National Institute for Health Research"]}},"HDBItheme":["BloodAndImmune"]},"ORCID:0000-0001-8843-7730":{"id":["ORCID:0000-0001-8843-7730"],"family_name":["Barker"],"personal_name":["Roger A."],"affiliations":{"ROR:013meh722":{"organization_name":["University of Cambridge"]},"ROR:05nz0zp31":{"organization_name":["Wellcome/MRC Cambridge Stem Cell Institute"]}}},"ORCID:0000-0001-6055-277X":{"id":["ORCID:0000-0001-6055-277X"],"family_name":["Bayraktar"],"personal_name":["Omer"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}},"ORCID:0000-0001-7577-3794":{"id":["ORCID:0000-0001-7577-3794"],"family_name":["Chédotal"],"personal_name":["Alain"],"affiliations":{"ROR:000zhpw23":{"organization_name":["Institut de la Vision"]},"ROR:029brtt94":{"organization_name":["Université Claude Bernard Lyon 1"]},"ROR:01502ca60":{"organization_name":["Hospices Civils de Lyon"]}},"HDBItheme":["BloodAndImmune"]},"ORCID:0000-0001-6924-6402":{"id":["ORCID:0000-0001-6924-6402"],"family_name":["Buckley"],"personal_name":["Christopher D."],"affiliations":{"ROR:052gg0110":{"organization_name":["University of Oxford"]}}},"ORCID:0000-0002-6294-6366":{"id":["ORCID:0000-0002-6294-6366"],"family_name":["Teichmann"],"personal_name":["Sarah A."],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]},"ROR:013meh722":{"organization_name":["University of Cambridge"]}}}},"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."],"HDBItheme":["BloodAndImmune"],"datasets":{"ArrayExpress:E-MTAB-14385":{"id":["ArrayExpress:E-MTAB-14385"],"title":["A Multi-omic Atlas of Human Embryonic Skeletal Development -Multiome GEX+ATAC"],"description":["Two distinct and anatomically restricted modes of ossification, which are endochondral ossification and intramembranous ossification, govern osteogenesis and joint formation throughout the human skeleton and, to our knowledge, the cellular bases by which they form and mature remain incompletely described in human development at single-cell resolution. To address this, we apply single-nuclei paired RNA and ATAC sequencing to decipher the molecular gene regulatory programmes that mediate maturation of the distinct bone and joint-forming niches in the cranium and appendicular skeleton across space and time from 5-11 PCW.\n \n Visium and ISS data are available for visualization and can be\n downloaded from https://developmental.cellatlas.io/skeleton-development."],"authors":{"ORCID:0000-0002-2066-7297":{"id":["ORCID:0000-0002-2066-7297"],"family_name":["Fei"],"personal_name":["Lijiang"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}},"AUTHTEMP:00059":{"id":["AUTHTEMP:00059"],"family_name":["To"],"personal_name":["Ken"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]},"ROR:013meh722":{"organization_name":["University of Cambridge"]}}},"ORCID:0000-0002-6294-6366":{"id":["ORCID:0000-0002-6294-6366"],"family_name":["Teichmann"],"personal_name":["Sarah A."],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]},"ROR:013meh722":{"organization_name":["University of Cambridge"]}}}},"tags":["spatial","imaging","sequencing"]}},"code":{"SWHID:swh:1:dir:521f5ebc748f098312488a3cff71a7a9124bda50":{"id":["SWHID:swh:1:dir:521f5ebc748f098312488a3cff71a7a9124bda50"],"title":["nf-fgwas"],"description":["Nextflow implementation of fGWAS for single cell data. The pipeline uses the hierarchical model from here and the application to single cell data has been described in detail here.\nIn brief, given a single cell dataset and GWAS summary statistics, fGWAS allows to find cell types that are enriched for the genetic associations. It requires full GWAS summary statistics, including logOR and standard error."],"authors":{"ORCID:0000-0002-5249-444X":{"id":["ORCID:0000-0002-5249-444X"],"family_name":["Pett"],"personal_name":["J. Patrick"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}}}},"SWHID:swh:1:dir:171dbb741f1941beeeeb00e00b8d6e797ee60a8b":{"id":["SWHID:swh:1:dir:171dbb741f1941beeeeb00e00b8d6e797ee60a8b"],"title":["snp2cell"],"description":["snp2cell is a package for identifying gene regulation involved in specific traits and cell types. It combines three elements: (i) GWAS summary statistics, (ii) single cell data and (iii) a base gene regulatory network.\nA network propagation approach is used to integrate and overlap different types of scores on the network. Random permutations of scores are then used to evaluate the significance of high scores.\nAs an output, a networkx graph of the gene regulatory network with integrated scores can be used to inspect gene regulatory programs that are linked to the trait (from GWAS) on a per cell type basis."],"authors":{"ORCID:0000-0002-5249-444X":{"id":["ORCID:0000-0002-5249-444X"],"family_name":["Pett"],"personal_name":["J. Patrick"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}}}},"SWHID:swh:1:dir:38676d9d74c442631f540144b31b1fe11d322964":{"id":["SWHID:swh:1:dir:38676d9d74c442631f540144b31b1fe11d322964"],"title":["A Multi-omic Atlas of Human Embryonic Skeletal Development"],"description":["These are scripts accompanying our manuscript: \"A multi-omic atlas of human embryonic skeletal development\""],"authors":{"ORCID:0000-0002-5249-444X":{"id":["ORCID:0000-0002-5249-444X"],"family_name":["Pett"],"personal_name":["J. Patrick"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}}}},"SWHID:swh:1:dir:06e3053b14fc3ac1da2e3b4340e6a6c5bf371be1":{"id":["SWHID:swh:1:dir:06e3053b14fc3ac1da2e3b4340e6a6c5bf371be1"],"title":["ISS (in situ sequencing) Patcher"],"description":["`iss_patcher` is a simple package for approximating features not experimentally captured in low-dimensional data based on related,  high-dimensional data. The shared feature space between the two objects is identified, and log-normalised and z-scored on a per-object basis. The nearest neighbours of the low-dimensional observations in the high-dimensional space are identified, and the counts of the absent features are approximated as the mean of the high-dimensional neighbours.\nWhile the function was initially written for processing ISS and GEX data, it can in principle be used for any sort of low-dimensional data featuring a subset of features from high-dimensional data."],"authors":{"ORCID:0000-0002-2586-9576":{"id":["ORCID:0000-0002-2586-9576"],"family_name":["Polański"],"personal_name":["Krzysztof"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}},"ORCID:0000-0002-5249-444X":{"id":["ORCID:0000-0002-5249-444X"],"family_name":["Pett"],"personal_name":["J. Patrick"],"affiliations":{"ROR:05cy4wa09":{"organization_name":["Wellcome Sanger Institute"]}}}}}}}