Molecular Pathogenic Mechanism of Rhabdomyosarcoma

横纹肌肉瘤的分子发病机制

• 批准号: 8157684
• 负责人: Liang Cao
• 金额: $ 25.47万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157684
• 关键词: Binding; Data; Data Set; Embryonic Development; FGFR4 gene; Genetic Enhancer Element; IGF1R gene; Molecular; PAX3 gene; PAX7 gene; Rhabdomyosarcoma; Validation

To understand the molecular pathogenic mechanism of PAX3-FKHR in the development of RMS, we used ChIP-seq to map PAX3-FKHR genomic binding sites associated with 1072 genes in RMS cells. I. The data shows that PAX3-FKHR binds to the same sites as PAX3 at enhancers for MYF5, FGFR4, as well as the MYOD core enhancer previously shown to be downstream of PAX3 regulation. Moreover, our dataset has the precision for a rapid identification and validation of novel and specific sequences required for the enhancer activity for MYOD and FGFR4. II. The genome wide analysis reveals that the vast majority of PAX3-FKHR sites are: 1) distal to transcription start sites; 2) conserved; 3) enriched for PAX3 motifs; 4) strongly associated with genes over-expressed in PAX3-FKHR positive RMS cells and tumors. There is little evidence in our dataset for PAX3-FKHR binding at the promoters. In one instance, our data establishes two intronic enhancer elements for MET, rather than at the previously described promoter. The genome-wide analysis further illustrates a strong association between PAX3 and E-box motifs in these binding sites, suggestive of a common co-regulation for many target genes. III. The map of PAX3-FKHR binding sites provides new links for PAX3 and PAX3-FKHR functions and new targets for RMS therapy. Our study identifies genes that are critically important for different aspects of limb-genesis, as direct PAX3-FKHR targets. Further, we identify IGF1R as a direct target for PAX3-FKHR. The dependence on IGF1R for survival in some RMS cells with PAX3-FKHR makes it an ideal therapeutic target for this cancer.

为了了解PAX3-FKHR在RMS开发中的分子致病机制，我们使用ChIP-Seq绘制与RMS细胞中1072个基因相关的PAX3-FKHR基因组结合位点。 I.数据表明，PAX3-FKHR与MyF5，FGFR4的增强子处的PAX3与PAX3相同的位点结合，以及先前显示为PAX3调节下游的MYOD核心增强子。此外，我们的数据集具有快速识别和验证MYOD和FGFR4所需的新颖和特定序列的精确度。 ii。基因组广泛的分析表明，绝大多数PAX3-FKHR位点是：1）转录起始位点； 2）保守； 3）富含PAX3图案； 4）与PAX3-FKHR阳性RMS细胞和肿瘤中过表达的基因密切相关。我们数据集中几乎没有证据表明启动子对PAX3-FKHR结合。在一个例子中，我们的数据为MET建立了两个内含子增强子元素，而不是在先前描述的启动子上。全基因组分析进一步说明了这些结合位点中PAX3与E-box基序之间的密切关联，这表明许多靶基因的共同共同调节。 iii。 PAX3-FKHR结合位点的地图为PAX3和PAX3-FKHR功能提供了新的链接，以及RMS治疗的新目标。我们的研究确定了对肢体生成的不同方面至关重要的基因，这是直接的PAX3-FKHR靶标。此外，我们将IGF1R识别为PAX3-FKHR的直接目标。对某些带有PAX3-FKHR的RMS细胞中IGF1R生存的依赖性使其成为该癌症的理想治疗靶标。