HOTAIR异常调控HoxD基因簇致先天性马蹄内翻足的分子机制

Congenital clubfoot (CCF) is a common congenital malformations which threat children health seriously. HoxD9-13 play a role in the hindlimb development, and HOTAIR, which expressed in the limb embryonic development, regulated the expression of HoxD8-11 by mediating inhibition histone H3K27 methylation in the epigenetic modifications.Our recent researches have revealed that the expression of HOTAIR distinctly higher in the foot skin flbroblast of CCF children than the normal children.We also found that retinoic acid upgraded the expression of HOTAIR in the stroma cells of rat hindlimb bud,while which markedly restrained the expression of HoxD9 and HoxD10 to delay the chondrocyte differentiation. In order to clarify the pathogenesis of CCF, our project analyze the epigenetics mechanism of HOTAIR and HoxD gene cluster by applying foot skin flbroblast of the CCF's children and the CCF's rat models.

先天性马蹄内翻足（CCF）是严重危害儿童健康的常见先天畸形。HoxD9-13在后（下）肢及足的发育中发挥作用，而HOTAIR能够通过介导抑制性组蛋白H3K27甲基化这一表观遗传修饰来调控HoxD8-11基因表达，HOTAIR在胚胎发育过程中又集中表达在足部。我们近期的研究结果表明：马蹄内翻足患儿足部皮肤成纤维细胞HOTAIR的表达明显高于正常人群；维甲酸上调大鼠后肢芽基质细胞HOTAIR的表达，显著抑制HoxD9、HoxD10的表达，延迟软骨分化。因此，本项目拟利用CCF患儿的患足原代成纤维细胞模型和我们率先构建的类CCF动物模型，系统分析HOTAIR与HoxD基因簇之间的因果关系和表观遗传学证据，阐明CCF的发病机制。

先天性马蹄内翻足（CCF）是严重危害儿童健康的常见先天畸形。HoxD9-13在后（下）肢及足的发育中发挥作用，而HOTAIR能够通过介导抑制性组蛋白H3K27甲基化这一表观遗传修饰来调控HoxD8-11基因表达，HOTAIR在胚胎发育过程中又集中表达在足部。我们近期的研究结果表明：马蹄内翻足患儿足部皮肤成纤维细胞HOTAIR的表达明显高于正常人群；维甲酸显著抑制上调大鼠后肢芽HoxD9、HoxD10的表达，延迟软骨分化。因此，本项目拟利用CCF患儿的患足原代成纤维细胞模型，系统分析HOTAIR与HoxD基因簇之间的因果关系和表观遗传学证据，阐明CCF的发病机制。