Leveraging single cell multiomic analyses to identify factors that drive human chondrocyte cell fate

Cartilage plays a crucial role in skeletal development and function, and abnormal development contributes to genetic and age-related skeletal disease. To better understand how human cartilage develops in vivo , we jointly profiled the transcriptome and open chromatin regions in individual nuclei recovered from distal femurs at 2 fetal timepoints. We used these multiomic data to identify transcription factors expressed in distinct chondrocyte subtypes, link accessible regulatory elements with gene expression, and predict transcription factor-based regulatory networks that are important for growth plate or epiphyseal chondrocyte differentiation. We developed a human pluripotent stem cell platform for interrogating the function of predicted transcription factors during chondrocyte differentiation and used it to test NFATC2 . We expect new regulatory networks we uncovered using multiomic data to be important for promoting cartilage health and treating disease, and our platform to be a useful tool for studying cartilage development in vitro .