Cowie Philip, Hay Elizabeth A, MacKenzie Alasdair
The School of Medical Sciences,Institute of Medical Sciences, University of Aberdeen,Foresterhill,Aberdeen AB25 2ZD,UK.
Expert Rev Mol Med. 2015 Jan 30;17:e4. doi: 10.1017/erm.2014.23.
Non-coding cis-regulatory sequences act as the 'eyes' of the genome and their role is to perceive, organise and relay cellular communication information to RNA polymerase II at gene promoters. The evolution of these sequences, that include enhancers, silencers, insulators and promoters, has progressed in multicellular organisms to the extent that cis-regulatory sequences make up as much as 10% of the human genome. Parallel evidence suggests that 75% of polymorphisms associated with heritable disease occur within predicted cis-regulatory sequences that effectively alter the 'perception' of cis-regulatory sequences or render them blind to cell communication cues. Cis-regulatory sequences also act as major functional targets of epigenetic modification thus representing an important conduit through which changes in DNA-methylation affects disease susceptibility. The objectives of the current review are (1) to describe what has been learned about identifying and characterising cis-regulatory sequences since the sequencing of the human genome; (2) to discuss their role in interpreting cell signalling pathways pathways; and (3) outline how this role may be altered by polymorphisms and epigenetic changes. We argue that the importance of the cis-regulatory genome for the interpretation of cellular communication pathways cannot be overstated and understanding its role in health and disease will be critical for the future development of personalised medicine.
非编码顺式调控序列充当基因组的“眼睛”，其作用是感知、组织并将细胞通讯信息传递给基因启动子处的RNA聚合酶II。这些序列（包括增强子、沉默子、绝缘子和启动子）在多细胞生物中的进化程度已使顺式调控序列占人类基因组的比例高达10%。平行证据表明，与遗传性疾病相关的多态性中有75%发生在预测的顺式调控序列内，这些序列会有效改变顺式调控序列的“感知”，或使其对细胞通讯信号视而不见。顺式调控序列也是表观遗传修饰的主要功能靶点，因此代表了DNA甲基化变化影响疾病易感性的重要途径。本综述的目的是：（1）描述自人类基因组测序以来在识别和表征顺式调控序列方面所学到的知识；（2）讨论它们在解读细胞信号通路中的作用；（3）概述这种作用可能如何因多态性和表观遗传变化而改变。我们认为，顺式调控基因组对细胞通讯通路解读的重要性再怎么强调都不为过，了解其在健康和疾病中的作用对于个性化医学的未来发展至关重要。
