Laboratory of Gene Regulation, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Bioessays. 2023 Oct;45(10):e2300047. doi: 10.1002/bies.202300047. Epub 2023 Jul 5.
Despite ever-increasing accumulation of genomic data, the fundamental question of how individual genes are switched on during development, lineage-specification and differentiation is not fully answered. It is widely accepted that this involves the interaction between at least three fundamental regulatory elements: enhancers, promoters and insulators. Enhancers contain transcription factor binding sites which are bound by transcription factors (TFs) and co-factors expressed during cell fate decisions and maintain imposed patterns of activation, at least in part, via their epigenetic modification. This information is transferred from enhancers to their cognate promoters often by coming into close physical proximity to form a 'transcriptional hub' containing a high concentration of TFs and co-factors. The mechanisms underlying these stages of transcriptional activation are not fully explained. This review focuses on how enhancers and promoters are activated during differentiation and how multiple enhancers work together to regulate gene expression. We illustrate the currently understood principles of how mammalian enhancers work and how they may be perturbed in enhanceropathies using expression of the α-globin gene cluster during erythropoiesis, as a model.
尽管基因组数据不断增加，但关于个体基因在发育、谱系特化和分化过程中是如何开启的基本问题尚未得到充分解答。人们普遍认为，这涉及至少三个基本调控元件的相互作用：增强子、启动子和绝缘子。增强子含有转录因子结合位点，这些结合位点由在细胞命运决定过程中表达的转录因子 (TFs) 和共因子结合，并通过其表观遗传修饰至少部分维持所施加的激活模式。该信息通过与增强子紧密物理接近形成包含高浓度 TF 和共因子的“转录枢纽”从增强子传递到其同源启动子。转录激活这些阶段的机制尚未得到充分解释。本篇综述重点关注增强子和启动子在分化过程中如何被激活，以及多个增强子如何协同调节基因表达。我们以哺乳动物珠蛋白基因簇在红细胞生成过程中的表达为例，说明了目前已知的哺乳动物增强子如何发挥作用，以及它们在增强子病中可能受到干扰的原理。
