The mechanism of transcriptional regulation of Runx2 gene and the program of skeletal development

Runx2基因转录调控机制与骨骼发育程序

• 批准号: 22249062
• 负责人: KOMORI Toshihisa
• 金额: $ 30.37万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-22249062/
• 关键词: Runx2; エンハンサー; 骨芽細胞; 転写制御; 間葉系幹細胞; Dlx5; Mef2; クロマチン修飾; トランスジェニックマウス; FGF; Wnt; Tcf7; 骨格形成; 軟骨細胞; 転写因子

Runx2 is an essential transcription factor for osteoblast differentiation at an early stage and chondrocyte differentiation at a late stage. To elucidate the mechanism of the transcriptional regulation of Runx2 gene, we generated GFP transgenic mice using the BAC clone of Runx2 gene locus. By deleting the BAC clone, we identified osteoblast-specific enhancer. The enhancer directed GFP expression specifically to osteoblasts. Dlx5/Dlx6, Mef2, Tcf7, Ctnnb1, Sp7, Smad1, and Sox5/Sox6, which localized on the enhancer region, synergistically upregulated the enhancer activity. Dlx5 and Mef2 directly bound to the enhancer, while the other factors bound to the enhancer by protein-protein interaction. Thus, Dlx5/Dlx6 and Mef2, which formed an enhanceosome with Tcf7, Ctnnb1, Sp7, Smad1, and Sox5/Sox6, play an essential role in the osteoblast-specific activation of the enhancer, leading to the differentiation of mesenchymal stem cells to osteoblasts.

Runx 2是早期成骨细胞分化和晚期软骨细胞分化的必需转录因子。为了阐明Runx 2基因的转录调控机制，我们利用Runx 2基因位点的BAC克隆构建了GFP转基因小鼠。通过删除BAC克隆，我们确定了成骨细胞特异性增强子。该增强子特异性地将GFP表达导向成骨细胞。位于增强子区域的Dlx 5/Dlx 6、Mef 2、Tcf 7、Ctnnb 1、Sp 7、Smad 1和Sox 5/Sox 6协同上调增强子活性。Dlx 5和Mef 2直接与增强子结合，而其他因子通过蛋白质-蛋白质相互作用与增强子结合。因此，Dlx 5/Dlx 6和Mef 2与Tcf 7、Ctnnb 1、Sp 7、Smad 1和Sox 5/Sox 6形成增强体，在成骨细胞特异性激活增强子中发挥重要作用，导致间充质干细胞分化为成骨细胞。

项目成果

骨芽細胞分化における抗アポトーシス分子Bcl-2の役割

抗凋亡分子Bcl-2在成骨细胞分化中的作用

• 发表时间: 2010
• 作者: Muraki S;Akune T;Ishimoto Y;Nagata K;Yoshida M;Tanaka S;Oka H;Kawaguchi H;Nakamura K;and Yoshimura N;森石武史
• 通讯作者: 森石武史

Regulation of Osteoblast Differentiation by Runx2

• DOI: 10.1007/978-1-4419-1050-9_5
• 发表时间: 2010-01-01
• 期刊: OSTEOIMMUNOLOGY: INTERACTIONS OF THE IMMUNE AND SKELETAL SYSTEMS II
• 作者: Komori, Toshihisa

Early onset of Runx2 expression caused craniosynostosis, ectopic bone formation, and limb defects

• DOI: 10.1016/j.bone.2011.07.023
• 发表时间: 2011-10-01
• 期刊: BONE
• 影响因子: 4.1
• 作者: Maeno, Takafumi;Moriishi, Takeshi;Komori, Toshihisa
• 通讯作者: Komori, Toshihisa

骨細胞ネットワークによるメカニカルストレス応答

骨细胞网络的机械应力响应

• 发表时间: 2013
• 作者: Masuyama R;Mizuno A;Komori H;Kajiya H;Uekawa A;Kitaura H;Okabe K;Ohyama K;Komori T;Nambu Y;Kagawa R;Tanaka K;Masuyama R;小守壽文
• 通讯作者: 小守壽文

Regulation of osteoblast differentiation and bone angiogenesis by RUNX2 and SP7.

RUNX2 和 SP7 对成骨细胞分化和骨血管生成的调节。

• 发表时间: 2010
• 作者: Mikasa M;Rokutanda S;Komori H;Ito K;Tsang YS;Date Y;Yoshida CA;Komori T;Moriishi T;Wang Y;Komori T;Hisa I;Ann EJ;Mikasa M;Komori T;小守壽文;王宇英;小守壽文
• 通讯作者: 小守壽文