Osteoblast plasticity during zebrafish regeneration

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Dedifferentiation of mature adult cells is a fascinating biological phenomenon that is essential for regeneration of a variety of organs, yet its regulation and molecular underpinnings are poorly understood. We have previously found that mature osteoblasts dedifferentiate to contribute to regeneration of bone in the zebrafish fin, a process that seems to set the highly regenerative zebrafish apart from mammals. We have also recently shown that NF-κB signaling acts cells autonomously within osteoblasts to inhibit their dedifferentiation, but we have not yet identified targets of the pathway mediating its role. Our preliminary unpublished data suggest that osteoblasts are highly heterogenous during fin homeostasis, during dedifferentiation and during redifferentiation in the regenerating fin. Here we propose to use single cell RNA-seq and ATAC-seq approaches to resolve osteoblast heterogeneity during homeostasis, dedifferentiation and redifferentiation, and to deduce transcriptional and chromatin landscape dynamics during dedifferentiation. In addition, we will identify downstream effectors of NF-κB signaling in osteoblasts. We expect that these powerful single cell approaches will reveal novel osteoblast biology by identifying previously uncharacterized subpopulations, and will result in molecular insight into the regulating of dedifferentiation.