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. Statement of SignificanceThe identity and integrity of the articular cartilage lining our joints are crucial to pain-free activities of daily living. Here we identified a gene regulatory landscape of human chondrogenesis at single cell resolution, which is expected to open new avenues of research aimed at mitigating cartilage diseases that affect hundreds of millions of individuals world-wide.