Dynamic regulation of Nanog and stem cell-signaling pathways by Hoxa1 during early neuro-ectodermal differentiation of ES cells
Dynamic regulation of Nanog and stem cell-signaling pathways by Hoxa1 during early neuro-ectodermal differentiation of ES cells
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DOI：
10.1073/pnas.1610612114
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发表时间：
2017-06-06
影响因子：
11.1
通讯作者：
Krumlauf, Robb
中科院分区：
文献类型：
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作者：
De Kumar, Bony;Parker, Hugo J.;Krumlauf, Robb
homobox a1 （Hoxa1）是胚胎干细胞分化诱导最快的基因之一，也是小鼠胚胎中最早表达的Hox基因。在这项研究中，我们使用基因组方法鉴定了胚胎干细胞向神经外胚层分化的早期阶段hoxa1结合区域。在维甲酸治疗的2小时内，Hoxa1被迅速招募到与多能性调控相关的基因位点，这些基因在表达上表现出早期的变化。Hoxa1的占用模式是动态的，并且随着时间的推移而变化。在分化的第12小时，许多在第2小时结合的位点丢失，出现了新的结合区域群。在这两个时间点上，全基因组图谱显示Nanog （Nanog homeobox）和Hoxa1在许多共同的目标位点上存在显著的共占用，并且这些位点与多能调控网络中的基因有关。除了共享靶基因外，Hoxa1结合到Nanog的调控区域，相反，Nanog结合到Hoxa1的3'增强子。这一发现为Hoxa1和Nanog之间通过相互抑制机制的直接交叉调节反馈提供了证据。Hoxa1还结合Sox2（性别决定区Y box 2）、Esrrb（雌激素相关受体β）和Myc的调控区域，这强调了其对多能调控网络核心成分的关键输入。我们提出了一个模型，即Nanog和Hoxa1对共享靶点的直接输入以及Hoxa1与核心多能性网络之间的相互抑制，提供了一种调节多能性和分化交替状态之间微妙平衡的分子机制。
Homeobox a1 (Hoxa1) is one of the most rapidly induced genes in ES cell differentiation and it is the earliest expressed Hox gene in the mouse embryo. In this study, we used genomic approaches to identify Hoxa1-bound regions during early stages of ES cell differentiation into the neuro-ectoderm. Within 2 h of retinoic acid treatment, Hoxa1 is rapidly recruited to target sites that are associated with genes involved in regulation of pluripotency, and these genes display early changes in expression. The pattern of occupancy of Hoxa1 is dynamic and changes over time. At 12 h of differentiation, many sites bound at 2 h are lost and a new cohort of bound regions appears. At both time points the genome-wide mapping reveals that there is significant co-occupancy of Nanog (Nanog homeobox) and Hoxa1 on many common target sites, and these are linked to genes in the pluripotential regulatory network. In addition to shared target genes, Hoxa1 binds to regulatory regions of Nanog, and conversely Nanog binds to a 3' enhancer of Hoxa1. This finding provides evidence for direct cross-regulatory feedback between Hoxa1 and Nanog through a mechanism of mutual repression. Hoxa1 also binds to regulatory regions of Sox2 (sex-determining region Y box 2), Esrrb (estrogen-related receptor beta), and Myc, which underscores its key input into core components of the pluripotential regulatory network. We propose a model whereby direct inputs of Nanog and Hoxa1 on shared targets and mutual repression between Hoxa1 and the core pluripotency network provides a molecular mechanism that modulates the fine balance between the alternate states of pluripotency and differentiation.