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首页> 外文期刊>Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research >Osterix and NO66 histone demethylase control the chromatin of osterix target genes during osteoblast differentiation
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Osterix and NO66 histone demethylase control the chromatin of osterix target genes during osteoblast differentiation

机译：Osterix和NO66组蛋白脱甲基酶控制成骨细胞分化过程中osterix目标基因的染色质

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摘要

Commitment of Runx2-expressing precursor osteoblasts to functional osteoblasts and then to 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 lysine 4 methyl transferase (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 nucleolar protein 66 (NO66), a 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 embryonic day 9.5 (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 DNA Methyltransferase 1A (DNMT1A), histone deacetylase 1A (HDAC1A), and HP1, which are known to control histone and DNA methylation. In addition, HP1 stimulated the demethylase activity of NO66 for its substrates "trimethylation of histone H3 at lysine 4" (H3K4me3) and "trimethylation of histone H3 at lysine 36" (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 multilayered control of the chromatin architecture of specific osteoblast genes.
机译：Osterix（Osx）触发了表达Runx2的前体成骨细胞对功能性成骨细胞然后对成骨细胞的承诺，后者在骨形成过程中激活了这些细胞中的靶基因。从成骨细胞到成骨细胞的过渡过程中，Osx是否在重塑其靶基因的染色质结构中发挥作用尚不清楚。在测试Osx对于活性染色质结构必不可少的假设时，我们首先显示在Osx空的颅盖细胞中，Osx处的转录激活因子（包括赖氨酸4甲基转移酶（Wdr5），c-Myc和H2A.Z）占据着。靶基因Bsp明显降低。在这些细胞的Bsp基因上，赖氨酸4和36的赖氨酸甲基化水平和组蛋白H3的乙酰化水平（活性染色质的标记）也降低了。相比之下，转录阻遏物HP1和核仁蛋白66（NO66）（先前被鉴定为与Osx相互作用的蛋白）的组蛋白去甲基化酶的占有率在无Osx的颅盖细胞中的Bsp基因处增加。此外，Bsp启动子在胚胎干（ES）细胞和胚胎第9.5天（E9.5）胚胎中被高度甲基化，但在E18.5胚胎的颅盖中被明显地低甲基化，这与强劲的Bsp表达相吻合。相比之下，与Osx野生型颅骨相比，Bsp启动子中的CpG甲基化在Osx无颅骨颅骨中保持较高水平。我们的数据还显示，NO66与DNA甲基转移酶1A（DNMT1A），组蛋白脱乙酰基酶1A（HDAC1A）和HP1相互作用，它们已知可控制组蛋白和DNA甲基化。此外，HP1对其底物“在赖氨酸4处的组蛋白H3三甲基化”（H3K4me3）和“在赖氨酸36处的组蛋白H3三甲基化”（H3K36me3）刺激了NO66的脱甲基酶活性。我们的发现强烈表明，在没有Osx的情况下，Osx目标基因的染色质是转录失活的。我们建议Osx是成骨细胞分化过程中活性染色质状态形成的分子开关，而NO66通过组蛋白去甲基化和/或阻遏物复合物的形成来帮助基因抑制，从而导致特定成骨细胞基因染色质结构的多层控制。

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