Dissecting the retinoid-induced differentiation of F9 embryonal stem cells by integrative genomics.
Dissecting the retinoid-induced differentiation of F9 embryonal stem cells by integrative genomics.
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DOI：
10.1038/msb.2011.73
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发表时间：
2011-10-11
影响因子：
9.9
通讯作者：
Gronemeyer, Hinrich
中科院分区：
文献类型：
--
作者：
Mendoza-Parra, Marco A.;Walia, Mannu;Sankar, Martial;Gronemeyer, Hinrich
关键词：
视黄酸（RA）通过激活包括视黄酸受体（RARα、β、γ）和类维生素A X受体（RXRα、β、γ）的异二聚体转录因子（TF）来触发生理过程。单个信号如何诱导高度复杂的时间控制网络，最终协调生理过程尚不清楚。使用RA诱导分化模型，我们定义了RARγ和RXRα全基因组结合模式的时间变化，并将其与转录调控相关联。出乎意料的是，两种受体都表现出高度动态结合，不同的RXRα异二聚体靶向相同的基因座。比较RARγ和RXRα在RA调节基因处的共结合，鉴定了用亚型选择性激动剂验证的推定的RXRα-RARγ靶基因。从TF靶基因信息和时间基因表达推断分化过程中的基因调控决定。该分析揭示了六种不同的共表达途径，其中RXRα-RARγ与转录激活相关，而Sox 2和Egr 1被预测为调节阻遏。最后，通过整合功能共引，重构RXRα-RARγ调控网络。我们的分析提供了一个动态的RA信号在细胞分化过程中，揭示RAR异源二聚体动力学和滥交，并预测决策，RA信号多样化到不同的基因调控程序。
Retinoic acid (RA) triggers physiological processes by activating heterodimeric transcription factors (TFs) comprising retinoic acid receptor (RARα, β, γ) and retinoid X receptor (RXRα, β, γ). How a single signal induces highly complex temporally controlled networks that ultimately orchestrate physiological processes is unclear. Using an RA-inducible differentiation model, we defined the temporal changes in the genome-wide binding patterns of RARγ and RXRα and correlated them with transcription regulation. Unexpectedly, both receptors displayed a highly dynamic binding, with different RXRα heterodimers targeting identical loci. Comparison of RARγ and RXRα co-binding at RA-regulated genes identified putative RXRα–RARγ target genes that were validated with subtype-selective agonists. Gene-regulatory decisions during differentiation were inferred from TF-target gene information and temporal gene expression. This analysis revealed six distinct co-expression paths of which RXRα–RARγ is associated with transcription activation, while Sox2 and Egr1 were predicted to regulate repression. Finally, RXRα–RARγ regulatory networks were reconstructed through integration of functional co-citations. Our analysis provides a dynamic view of RA signalling during cell differentiation, reveals RAR heterodimer dynamics and promiscuity, and predicts decisions that diversify the RA signal into distinct gene-regulatory programs.
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影响因子：
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作者：
Garcia-Bassets, Ivan;Kwon, Young-Soo;Rosenfeld, Michael G.
通讯作者：
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影响因子：
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通讯作者：
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