MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK; Edinburgh Super Resolution Imaging Consortium (ESRIC), Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
Mol Cell. 2019 Nov 7;76(3):473-484.e7. doi: 10.1016/j.molcel.2019.07.038. Epub 2019 Sep 4.
Enhancers can regulate the promoters of their target genes over very large genomic distances. It is widely assumed that mechanisms of enhancer action involve the reorganization of three-dimensional chromatin architecture, but this is poorly understood. The predominant model involves physical enhancer-promoter interaction by looping out the intervening chromatin. However, studying the enhancer-driven activation of the Sonic hedgehog gene (Shh), we have identified a change in chromosome conformation that is incompatible with this simple looping model. Using super-resolution 3D-FISH and chromosome conformation capture, we observe a decreased spatial proximity between Shh and its enhancers during the differentiation of embryonic stem cells to neural progenitors. We show that this can be recapitulated by synthetic enhancer activation, is impeded by chromatin-bound proteins located between the enhancer and the promoter, and appears to involve the catalytic activity of poly (ADP-ribose) polymerase. Our data suggest that models of enhancer-promoter communication need to encompass chromatin conformations other than looping.
增强子可以在非常大的基因组距离上调节其靶基因的启动子。人们普遍认为，增强子作用的机制涉及三维染色质结构的重排，但这一点知之甚少。主要模型涉及通过环出中间染色质的物理增强子-启动子相互作用。然而，在研究 Sonic hedgehog 基因 (Shh) 的增强子驱动激活时，我们已经确定了一种与这种简单的环化模型不兼容的染色体构象变化。我们使用超分辨率 3D-FISH 和染色体构象捕获技术，观察到在胚胎干细胞向神经祖细胞分化过程中，Shh 与其增强子之间的空间接近性降低。我们表明，通过合成增强子激活可以再现这种情况，并且受到位于增强子和启动子之间的染色质结合蛋白的阻碍，并且似乎涉及多聚 (ADP-核糖) 聚合酶的催化活性。我们的数据表明，增强子-启动子通讯模型需要包含除环化以外的其他染色质构象。
