Genome-wide analysis of gene switch in cartilage formation

Abnormal development of cartilage tissue causes infant limb malformation. Destruction of joint cartilage is tremendously harmful for the patients with diseases such as rheumatoid arthritis. Regenerative and/or transplantational therapy for cartilage might solve these problems, however, the molecular mechanisms of regulation of chondrocytic differentiation have not been fully elucidated. Chondrogenesis is a multi-step proccess in which multi-potent mesenchymal stem cells differentiate into chondrocytes. The transcription factor Sox9 regulates chondrocyte differentiation and cartilage-specific expression of genes, such as Col2a1. However, Sox9 expression is detected not only in chondrogenic tissue but also in non-chondrogenic tissues, suggesting the existence of a molecular partner(s) required for Sox9 to control chondrogenesis and chondrogenic gene expression. Then, we demonstrated that Smad3 and PGC-1Ą regulate Col2a1 expression by associating with Sox9 and p300. Many co-fators have the potential to interact with multiple transcription factors and regulate their activities. Thus, in addition to Sox9, PGC-1Ą may regulate other chondrogenesis-related transcription factors. Then, the gene expression pattern of every transcription factors and co-factors which might act as the "gene switches" in embryogenesis is analyzed by the whole-mount in situ hybridization method in rodent embryos. These results of spatial appearance information shall be built into an expressional database. The role of chromatin and its epigenetic modifications which could be reffered as an alternative genetic codes in cartilage development might be clarified by the above-mentioned genome-wide analysis, and we will pursue these basic molecular mechanisms that foundate the future medical treatment such as cartilage regeneration.