DNA甲基化及组蛋白去乙酰化对Pitx1基因在后肢软骨发育中的表达调控

Congenital clubfoot (CCF) is a genetic disorders, caused by both inherit and environmental factors which both DNA methylation and histone deacetylation participate in the regulation of gene expression and the influence of chromatin structure. However,Pitx1 gene is closely related to the development and shape of posterior limb. DNA methylation and histone deacetylation can inhibit the activity of Pitx1 together, further affects the expression of key genes of cartilage development in rat hind limbs and cause skeletal deformities. Surprisingly, the reliably and stably animal model we established is well consistent with human CCF.So, we proposed that it can be elucidated the possible pathogenesis of CCF in epigenetics by detecting the methylation of Pitx1 gene and the acetylation of histone and further analysising the DNMT-3b and HDAC in the hind limb bud from very early rat embryos after ATRA treatment in vivo and in vitro. Our results may provide a theoretical basis for for the prevention of CCF, prenatal diagnosis and possible prenatal intervention measures.

先天性马蹄内翻足（CCF）是一种由遗传因素和环境致畸因素共同作用，DNA甲基化及组蛋白去乙酰化共同参与基因表达的调控和影响染色质的结构，引起的遗传疾病。Pitx1基因与下肢的发育及成形密切相关。我们研究表明，DNA甲基化与组蛋白去乙酰化协同作用抑制Pitx1的活性，进而影响后肢软骨发育关键基因的表达，导致后肢骨骼畸形发生。我们长期构建稳定的动物模型与人类新生儿先天性马蹄足有较好的一致性，我们拟通过大鼠胚胎CCF模型，对ATRA处理后的早期胚胎体内和体外后肢芽组织进行Pitx1基因DNA甲基化位点及组蛋白乙酰化检测，并进一步对其甲基转移酶-3b （DNMT-3b）及组蛋白去乙酰化酶(HDACs)进行分析，从表观遗传学的角度阐明CCF的可能发病机制，为CCF的预防、产前诊断及可能的产前干预措施提供理论依据。

先天性马蹄内翻足（CCF）是一种由遗传因素和环境致畸因素共同作用，DNA甲基化及组蛋 白去乙酰化共同参与基因表达的调控和影响染色质的结构，引起的遗传疾病。Pitx1基因与下肢的发育及成形密切相关。我们研究表明，DNA甲基化与组蛋白去乙酰化协同作用抑制Pitx1的活性，进而影响后肢软骨发育关键基因的表达，导致后肢骨骼畸形发生。通过大鼠胚胎CCF模型，对ATRA处理后的早期胚胎体内和体外后肢芽组织进行Pitx1基因DNA甲基化位点及组蛋白乙酰化检测，并进一步对其甲基转移酶-3b （DNMT-3b）及组蛋白去乙酰化酶(HDACs)进行分析，从表观遗传学的角度阐明CCF的可能发病机制，为CCF的预防、产前诊断及可能的产前干预措施提供理论依据。

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