DNA methylation of the RUNX2 P1 promoter mediates MMP13 transcription in chondrocytes.
DNA methylation of the RUNX2 P1 promoter mediates MMP13 transcription in chondrocytes.
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DOI：
10.1038/s41598-017-08418-8
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发表时间：
2017-08-10
影响因子：
4.6
通讯作者：
Oreffo ROC
中科院分区：
文献类型：
--
作者：
Takahashi A;de Andrés MC;Hashimoto K;Itoi E;Otero M;Goldring MB;Oreffo ROC
Runt相关转录因子2（RUNX 2）对于骨形成以及软骨细胞成熟至关重要。基质金属蛋白酶（MMP）-13是骨关节炎（OA）中软骨降解的主要贡献者。我们和其他人已经表明，骨关节炎软骨细胞中MMP 13基因的异常表达是由近端启动子特定CpG位点的DNA甲基化状态变化以及不同反式激活因子（包括RUNX 2）的作用控制的。本研究旨在确定在OA软骨细胞中RUNX 2启动子中特定CpG位点的甲基化状态对RUNX 2驱动的MMP 13基因表达的影响。我们观察到MMP 13 mRNA水平和RUNX 2基因表达在人OA软骨细胞中的显著相关性。RUNX 2过表达增强MMP 13启动子活性，独立于MMP 13启动子甲基化状态。OA软骨细胞中RUNX 2 mRNA水平与RUNX 2 P1启动子中CpG位点甲基化百分比呈显著负相关。因此，野生型RUNX 2启动子的活性在体外甲基化处理后降低。我们的结论是，RUNX 2基因转录调控的启动子中的特定CpG位点的甲基化状态，并可能决定RUNX 2在OA软骨中的基因，如MMP 13的反式激活的可用性。
The Runt-related transcription factor 2 (RUNX2) is critical for bone formation as well as chondrocyte maturation. Matrix metalloproteinase (MMP)-13 is a major contributor to cartilage degradation in osteoarthritis (OA). We and others have shown that the abnormal MMP13 gene expression in OA chondrocytes is controlled by changes in the DNA methylation status of specific CpG sites of the proximal promoter, as well as by the actions of different transactivators, including RUNX2. The present study aimed to determine the influence of the methylation status of specific CpG sites in the RUNX2 promoter on RUNX2-driven MMP13 gene expression in OA chondrocytes. We observed a significant correlation between MMP13 mRNA levels and RUNX2 gene expression in human OA chondrocytes. RUNX2 overexpression enhanced MMP13 promoter activity, independent of the MMP13 promoter methylation status. A significant negative correlation was observed between RUNX2 mRNA levels in OA chondrocytes and the percentage methylation of the CpG sites in the RUNX2 P1 promoter. Accordingly, the activity of the wild type RUNX2 promoter was decreased upon methylation treatment in vitro. We conclude that RUNX2 gene transcription is regulated by the methylation status of specific CpG sites in the promoter and may determine RUNX2 availability in OA cartilage for transactivation of genes such as MMP13.
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影响因子：
7.6
作者：
Jonason JH;Xiao G;Zhang M;Xing L;Chen D
通讯作者：
Chen D
影响因子：
2.3
作者：
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Oreffo RO
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作者：
Ducy, P;Zhang, R;Karsenty, G
通讯作者：
Karsenty, G
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作者：
Chen, Carol G.;Thuillier, Daniel;Chin, Emily N.;Alliston, Tamara
通讯作者：
Alliston, Tamara
影响因子：
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作者：
Hashimoto, Ko;Oreffo, Richard O. C.;Gibson, Marc B.;Goldring, Mary B.;Roach, Helmtrud I.
通讯作者：
Roach, Helmtrud I.