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首页> 外文期刊>Molecular and Cellular Biology >Comparison of Genome-Wide Binding of MyoD in Normal Human Myogenic Cells and Rhabdomyosarcomas Identifies Regional and Local Suppression of Promyogenic Transcription Factors
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Comparison of Genome-Wide Binding of MyoD in Normal Human Myogenic Cells and Rhabdomyosarcomas Identifies Regional and Local Suppression of Promyogenic Transcription Factors

机译：正常人成肌细胞和横纹肌肉瘤中MyoD的全基因组结合的比较确定了早生转录因子的区域和局部抑制。

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摘要

Rhabdomyosarcoma is a pediatric tumor of skeletal muscle that expresses the myogenic basic helix-loop-helix protein MyoD but fails to undergo terminal differentiation. Prior work has determined that DNA binding by MyoD occurs in the tumor cells, but myogenic targets fail to activate. Using MyoD chromatin immunoprecipitation coupled to high-throughput sequencing and gene expression analysis in both primary human muscle cells and RD rhabdomyosarcoma cells, we demonstrate that MyoD binds in a similar genome-wide pattern in both tumor and normal cells but binds poorly at a subset of myogenic genes that fail to activate in the tumor cells. Binding differences are found both across genomic regions and locally at specific sites that are associated with binding motifs for RUNX1, MEF2C, JDP2, and NFIC. These factors are expressed at lower levels in RD cells than muscle cells and rescue myogenesis when expressed in RD cells. MEF2C is located in a genomic region that exhibits poor MyoD binding in RD cells, whereas JDP2 exhibits local DNA hypermethylation in its promoter in both RD cells and primary tumor samples. These results demonstrate that regional and local silencing of differentiation factors contributes to the differentiation defect in rhabdomyosarcomas.
机译：横纹肌肉瘤是一种骨骼肌小儿肿瘤，表达肌原性基本的螺旋-环-螺旋蛋白MyoD，但无法进行终末分化。先前的工作已经确定，MyoD的DNA结合发生在肿瘤细胞中，但是肌原性靶标无法激活。使用MyoD染色质免疫沉淀结合高通量测序和原代人肌肉细胞和RD横纹肌肉瘤细胞中的基因表达分析，我们证明MyoD在肿瘤细胞和正常细胞中均以相似的全基因组模式结合，但在一部分在肿瘤细胞中无法激活的成肌基因。在整个基因组区域和与RUNX1，MEF2C，JDP2和NFIC的结合基序相关的特定位点均存在结合差异。这些因子在RD细胞中的表达水平低于肌肉细胞，当在RD细胞中表达时可以挽救肌发生。 MEF2C位于在RD细胞中表现出较差的MyoD结合的基因组区域，而JDP2在RD细胞和原发性肿瘤样品中的启动子中均表现出局部DNA超甲基化。这些结果表明，分化因子的区域和局部沉默导致横纹肌肉瘤的分化缺陷。

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