Marco Angelozzi

Significance Cartilage is essential in vertebrate development and adulthood. Cartilage growth plates ensure skeletal growth until closing at puberty, and articular cartilage ensures lifelong structural and functional integrity of joints. Chondrocytes build cartilage in development, governed by the transcription factor SOX9. Using mouse models and transcriptome profiling approaches, we show here that SOX9 also has key roles to maintain growth plates open postnatally and to protect adult articular cartilage from osteoarthritic degradation. In particular, SOX9 safeguards the lineage fate of chondrocytes by preventing their dedifferentiation into skeletogenic mesenchymal progenitors followed by redifferentiation into osteoblasts. These findings provide insights into cellular plasticity and its molecular control in developmental, physiological, and pathological processes within and beyond the skeletal system.

ABSTRACT SOX9 controls cell lineage fate and differentiation in major biological processes. It is known as a potent transcriptional activator of differentiation-specific genes, but its earliest targets and its contribution to priming chromatin for gene activation remain unknown. Here, we address this knowledge gap using chondrogenesis as a model system. By profiling the whole transcriptome and the whole epigenome of wild-type and Sox9-deficient mouse embryo limb buds, we uncover multiple structural and regulatory genes, including Fam101a, Myh14, Sema3c and Sema3d, as specific markers of precartilaginous condensation, and we provide evidence of their direct transactivation by SOX9. Intriguingly, we find that SOX9 helps remove epigenetic signatures of transcriptional repression and establish active-promoter and active-enhancer marks at precartilage- and cartilage-specific loci, but is not absolutely required to initiate these changes and activate transcription. Altogether, these findings widen our current knowledge of SOX9 targets in early chondrogenesis and call for new studies to identify the pioneer and transactivating factors that act upstream of or along with SOX9 to prompt chromatin remodeling and specific gene activation at the onset of chondrogenesis and other processes.