JmjC domain-containing protein KDM6B, autosomal gene (JMJD3) is a recently identified histone H3 lysine 27 trimethylation (H3K27me3) demethylase and counteracts Polycomb-mediated transcription repression. However, the function of JMJD3 in vivo is still not well understood. A team of scientists led by Dr. Charlie Degui Chen from the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences, has uncovered a critical role of JMJD3 during endochondral ossification.
Most skeletal elements of our body are formed through endochondral bone formation, which starts from the differentiation of condensed mesenchymal cells to chondrocytes. Subsequently, chondrocytes undergoes proliferation, hypertrophy and shapes into the cartilage templates of future bones. Dysregulation of these processes will lead to severe chondrodysplasia and skeletal malformation diseases. To date, runt-related transcription factor RUNX2 is the identified master regulator of chondrocyte proliferation and hypertrophy. Runx2 null mice display severe chondrodysplasia with decreased proliferation and lack or delayed hypertrophy of chondrocytes. Conversely, overexpression of Runx2 in chondrocytes induces premature hypertrophy of chondrocytes and acceleration of endochondral ossification.
To help elucidate the roles of JMJD3 in vivo, the scientists generated Jmjd3 deficient mice and investigated them at different levels. Using alcian blue and alizarin red staining of skeletal preparations, they observed markedly delayed endochondral ossification in Jmjd3 deficient mice. By histology and in situ hybridization investigations, they detected the delayed endochondral ossification is primary associated with the severely decreased proliferation and delayed hypertrophy of chondrocytes in Jmjd3 null mice. These finding is reminiscent of the function of RUNX2 in chondrocytes maturation. Therefore, they generated double heterozygous of Jmjd3 and Runx2 mice and demonstrated that JMJD3 genetically cooperates with RUNX2 to promote chondrocyte proliferation, hypertrophy and thus endochondral ossification. They subsequently performed co-immunoprecipitation and chromatin immunoprecipitation and detected JMJD3 biochemically interacted with and enhanced RUNX2 protein activity to favor the expression of Runx2 and Ihh genes.
Researchers proposed JMJD3 acts as a coactivator of RUNX2 to promote chondrocyte proliferation and hypertrophy. “These findings provide important and new information for our understanding of mechanism of skeletal development via epigenetic regulation”. said Charlie Degui Chen.
This study entitled “JMJD3 promotes chondrocyte proliferation and hypertrophy during endochondral bone formation in mice” was published online on 2015 Jan 13 in Journal of Molecular Cell Biology.
This work was funded by the National Natural Science Foundation of China (91219304), National Basic Research Program of China (2010CB529705, 2011CB510103, 2014CB943100), and the Council of Shanghai Municipal Government for Science and Technology.
CONTACT:
Charlie Degui Chen, Principal Investigator
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Shanghai 200031, China
Phone: +86 21 54921148
E-mail: cdchen@@sibcb.ac.cn
Fig. Alizarin red (bone mineralization) and alcian blue (cartilage) stained skeleton of E18.5 wild type and Jmjd3 null littermates. (Image provided by Prof. Charlie Degui Chen`s group).
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