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Wein et al. Histone HDAC5 regulates sclerostin expression in osteocytes
DOI:10.1038/bonekey.2015.73
Wein et al. explored the molecular mechanisms underlying expression of the gene SOST, which encodes sclerostin, a known inhibitor of bone formation and an attractive drug target in osteoporosis.
They showed that histone deacetylase 5 (HDAC5) inhibits the expression of SOST in vitro in the Ocy454 murine cell line. Furthermore, when HDAC5 knockout mice were generated, their levels of SOST mRNA were significantly higher than in wild type mice and they exhibited reduced osteoblastic bone formation. They also had a greater number of sclerostin positive osteocytes, reduced trabecular bone density and low Wnt activity.
HDAC5 was shown to bind to, and inhibit, MEF2C, a transcription factor crucial for SOST expression. The authors used chromatin immunoprecipitation to map the binding site for MEF2C to an intergenic enhancer 45 kB downstream distally from the transcription start site within the SOST gene. They propose that HDAC5 recruits NcoR and HDAC3 (both corepressors) to this site, so preventing expression of the SOST gene. As osteocytes differentiate, occupancy of HDAC5 reduces, allowing MEF2C with its coactivator p300 to bind, allowing SOST expression to increase.
Editor’s comment: Importantly for human clinical study and drug development, a large genome-wide association study meta-analysis has shown that variants in both HDAC5 and MEF2C are important in the regulation of human bone mineral density.
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