Appropriate developmental gene regulation relies on the capacity of gene promoters to integrate inputs from distal regulatory elements, yet how this is achieved remains poorly understood. In embryonic stem cells (ESCs), a subset of silent developmental gene promoters are primed for activation by FBXL19, a CpG island binding protein, through its capacity to recruit CDK-Mediator. How mechanistically these proteins function together to prime genes for activation during differentiation is unknown. Here we discover that in mouse ESCs FBXL19 and CDK-Mediator support long-range interactions between silent gene promoters that rely on FBXL19 for their induction during differentiation and gene regulatory elements. During gene induction, these distal regulatory elements behave in an atypical manner, in that the majority do not acquire histone H3 lysine 27 acetylation and no longer interact with their target gene promoter following gene activation. Despite these atypical features, we demonstrate by targeted deletions that these distal elements are required for appropriate gene induction during differentiation. Together these discoveries demonstrate that CpG-island associated gene promoters can prime genes for activation by communicating with atypical distal gene regulatory elements to achieve appropriate gene expression.

中文翻译：

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CDK-Mediator和FBXL19通过促进非典型调节相互作用来激活启动基因。

适当的发育基因调控依赖于基因启动子整合来自远端调控元件的输入的能力，但是如何实现这一点仍知之甚少。在胚胎干细胞（ESC）中，沉默的发育基因启动子的一个子集因其募集CDK-介体的能力而被FBXL19（一种CpG岛结合蛋白）激活。这些蛋白质在分化过程中如何共同作用以激活基因，在机制上尚不清楚。在这里，我们发现，在小鼠胚胎干细胞中，FBXL19和CDK-Mediator支持在分化过程中依赖FBXL19诱导的沉默基因启动子与基因调控元件之间的远程相互作用。在基因诱导过程中，这些远端调控元件以非典型方式发挥作用，因为大多数不获得组蛋白H3赖氨酸27乙酰化，并且在基因激活后不再与其目标基因启动子相互作用。尽管有这些非典型特征，但我们通过有针对性的缺失证明了这些远端元件是分化过程中适当的基因诱导所必需的。这些发现共同证明，CpG-岛相关的基因启动子可以通过与非典型的远端基因调控元件进行通讯来启动激活基因，从而实现适当的基因表达。