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10.1002/jbmr.2103

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C3961497!3961497!24115157
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pmid24115157      J+Bone+Miner+Res 2014 ; 29 (4): 855-65
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  • Osterix and NO66 histone demethylase control the chromatin architecture of Osterix target genes during osteoblast differentiation #MMPMID24115157
  • Sinha KM; Yasuda H; Zhou X; deCrombrugghe B
  • J Bone Miner Res 2014[Apr]; 29 (4): 855-65 PMID24115157show ga
  • Commitment of Runx2-expressing precursor osteoblasts to functional osteoblasts and then osteocytes is triggered by Osterix (Osx), which activates its target genes in those cells during bone formation. It is not yet known whether Osx has a role in remodeling the chromatin architecture of its target genes during the transition from preosteoblast to osteoblast. In testing the hypothesis that Osx is indispensable for active chromatin architecture, we first showed that in Osx-null calvarial cells occupancy of the transcriptional activators including Wdr5, c-Myc and H2A.Z at the Osx-target gene Bsp was very markedly decreased. The levels of methylation of lysines 4 and 36 and acetylation of histone H3, markers for active chromatin, were also reduced at the Bsp gene in these cells. In contrast, occupancy of the transcriptional repressors HP1 and the NO66 histone demethylase, previously identified as an Osx-interacting protein, was increased at the Bsp gene in Osx-null calvarial cells. Furthermore, the Bsp promoter was hypermethylated in embryonic stem (ES) cells and in E9.5 embryos but was markedly hypomethylated in the calvaria of E18.5 embryos, coinciding with robust Bsp expression. In contrast, CpG methylation in the Bsp promoter remained high in Osx-null calvaria compared to Osx-wild type calvaria. Our data also revealed that NO66 interacted with DNMT1A and HDAC1A as well as HP1, which are known to control the histone and DNA methylation. In addition, HP1 stimulated the demethylase activity of NO66 for its substrates H3K4me3 and H3K36me3. Our findings strongly suggest that in the absence of Osx, the chromatin of Osx-target genes is transcriptionally inactive. We propose that Osx is a molecular switch for the formation of an active chromatin state during osteoblast differentiation, whereas NO66 helps gene repression through histone demethylation and/or formation of a repressor complex resulting in multi-layered control of the chromatin architecture of specific osteoblast genes.
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