An Orthologous Epigenetic Gene Expression Signature Derived from Differentiating Embryonic Stem Cells Identifies Regulators of Cardiogenesis.
An Orthologous Epigenetic Gene Expression Signature Derived from Differentiating Embryonic Stem Cells Identifies Regulators of Cardiogenesis.
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DOI：
10.1371/journal.pone.0141066
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Michelson AM
中科院分区：
文献类型：
--
作者：
Busser BW;Lin Y;Yang Y;Zhu J;Chen G;Michelson AM
在这里，我们在多物种框架内使用预测基因表达特征来识别在分化胚胎干细胞中决定心脏细胞命运的基因。我们发现，重叠的orthopathic小鼠和人类基因是最准确的候选心源性基因，因为这些基因确定了最保守的发育途径，心脏谱系的特点。一项基于RNAi的果蝇候选基因筛选发现了许多新的心源性基因。shRNA敲除结合新鉴定的转录因子锌指蛋白503和锌指E-box结合同源框2以及众所周知的心脏调节因子NK 2同源框5的转录组分析显示，锌指E-box结合同源框5与锌指蛋白503和锌指E-box结合同源框2的转录组分析相结合。框结合同源框2激活心肌细胞结构和功能所需的终末分化基因，而锌指蛋白503和NK 2同源框5是心肌细胞结构和功能所需的。心脏谱系的特化。我们进一步证明了NK 2同源框5和锌指蛋白503在心脏谱系的特化中的重要作用是抑制替代细胞命运特征的基因表达程序。总的来说，这些结果表明，orthopathy基因表达签名可以用来识别保守的心源性途径。
Here we used predictive gene expression signatures within a multi-species framework to identify the genes that underlie cardiac cell fate decisions in differentiating embryonic stem cells. We show that the overlapping orthologous mouse and human genes are the most accurate candidate cardiogenic genes as these genes identified the most conserved developmental pathways that characterize the cardiac lineage. An RNAi-based screen of the candidate genes in Drosophila uncovered numerous novel cardiogenic genes. shRNA knockdown combined with transcriptome profiling of the newly-identified transcription factors zinc finger protein 503 and zinc finger E-box binding homeobox 2 and the well-known cardiac regulatory factor NK2 homeobox 5 revealed that zinc finger E-box binding homeobox 2 activates terminal differentiation genes required for cardiomyocyte structure and function whereas zinc finger protein 503 and NK2 homeobox 5 are required for specification of the cardiac lineage. We further demonstrated that an essential role of NK2 homeobox 5 and zinc finger protein 503 in specification of the cardiac lineage is the repression of gene expression programs characteristic of alternative cell fates. Collectively, these results show that orthologous gene expression signatures can be used to identify conserved cardiogenic pathways.