Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.
J Biol Chem. 2022 Aug;298(8):102117. doi: 10.1016/j.jbc.2022.102117. Epub 2022 Jun 9.
In mammalian organisms, enhancers can regulate transcription from great genomic distances. How enhancers affect distal gene expression has been a major question in the field of gene regulation. One model to explain how enhancers communicate with their target promoters, the chromatin looping model, posits that enhancers and promoters come in close spatial proximity to mediate communication. Chromatin looping has been broadly accepted as a means for enhancer-promoter communication, driven by accumulating in vitro and in vivo evidence. The genome is now known to be folded into a complex 3D arrangement, created and maintained in part by the interplay of the Cohesin complex and the DNA-binding protein CTCF. In the last few years, however, doubt over the relationship between looping and transcriptional activation has emerged, driven by studies finding that only a modest number of genes are perturbed with acute degradation of looping machinery components. In parallel, newer models describing distal enhancer action have also come to prominence. In this article, we explore the emergence and development of the looping model as a means for enhancer-promoter communication and review the contrasting evidence between historical gene-specific and current global data for the role of chromatin looping in transcriptional regulation. We also discuss evidence for alternative models to chromatin looping and their support in the literature. We suggest that, while there is abundant evidence for chromatin looping as a major mechanism for enhancer function, enhancer-promoter communication is likely mediated by more than one mechanism in an enhancer- and context-dependent manner.
在哺乳动物生物中，增强子可以从很远的基因组距离调控转录。增强子如何影响远端基因表达一直是基因调控领域的一个主要问题。一种解释增强子如何与它们的靶启动子进行通讯的模型，染色质环化模型，假设增强子和启动子在空间上接近，以介导通讯。染色质环化已被广泛接受为增强子-启动子通讯的一种手段，这是由体外和体内证据积累驱动的。现在已知基因组折叠成一个复杂的 3D 排列，部分是由 Cohesin 复合物和 DNA 结合蛋白 CTCF 的相互作用创建和维持的。然而，在过去的几年中，由于研究发现只有少数基因受到环化机制成分急性降解的干扰，因此对环化与转录激活之间关系的怀疑出现了。与此同时，描述远端增强子作用的新模型也开始受到关注。在本文中，我们探讨了作为增强子-启动子通讯手段的环化模型的出现和发展，并回顾了历史上基因特异性和当前全局数据在染色质环化在转录调控中的作用之间的对比证据。我们还讨论了替代染色质环化的模型及其在文献中的支持证据。我们认为，虽然有大量证据表明染色质环化是增强子功能的主要机制，但增强子-启动子的通讯可能以增强子和上下文依赖的方式通过多种机制介导。
