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Ethanol Effects on Transcription Factor Network Regulating Stem Cell Differentiation

机译:乙醇对转录因子网络调控干细胞分化的影响

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This study probes the effects of ethanol on the molecular mechanisms regulating the differentiation of embryonic stem (ES) cells towards neuroectodermal state, which may be responsible for the abnormalities observed in fetal alcohol spectrum disorders (FASD). The effects of ethanol on the early phase of ES cell differentiation have not been well characterized. Here, we investigate the stage-specific action of ethanol during early embryogenesis by an integrated experimental and computational modeling approach. Our experimental system consists of mouse ES cells and directed differentiation to neuroectodermal fate in the presence of ethanol. Experimental single-cell multiplex data on the expression of the ES core transcription factors (TFs), Sox2, Oct4 and Nanog were obtained simultaneously by multicolor flow cytometry in live cells. Singlecell flow cytometric data were analyzed by ARACNE probabilistic modeling to construct transcriptional regulatory networks and quantify the TFs interactions in a pairwisemanner. Our analysis indicates that during differentiation towards neuroectodermal fate ethanol accelerates (i) the decline of the expression levels of Sox2 and Nanog, and (ii) the decreasing strength of the correlative interactions between the core TFs which is also reflected in (iii) an advanced differentiation phenotype.
机译:这项研究探讨了乙醇对调节胚胎干(ES)细胞向神经外胚层状态分化的分子机制的影响,这可能是胎儿酒精光谱异常(FASD)中观察到的异常现象的原因。乙醇对ES细胞分化的早期阶段的影响尚未得到很好的表征。在这里,我们通过集成的实验和计算模型方法,研究了早期胚胎发生过程中乙醇的阶段特异性作用。我们的实验系统由小鼠ES细胞组成,并在乙醇存在下定向分化为神经外胚层命运。通过多色流式细胞术同时在活细胞中获得了有关ES核心转录因子(TFs),Sox2,Oct4和Nanog表达的实验性单细胞多路复用数据。通过ARACNE概率模型分析单细胞流式细胞仪数据,以构建转录调控网络并以成对方式定量TFs相互作用。我们的分析表明,在向神经外皮命运的分化过程中,乙醇会加速(i)Sox2和Nanog表达水平的下降,以及(ii)核心TF之间相关相互作用的强度下降,这也反映在(iii)先进的分化表型。

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