Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA.
BMC Genomics. 2018 Dec 18;19(1):947. doi: 10.1186/s12864-018-5335-0.
The regulatory landscape of a gene locus often consists of several functionally redundant enhancers establishing phenotypic robustness and evolutionary stability of its regulatory program. However, it is unclear what mechanisms are employed by redundant enhancers to cooperatively orchestrate gene expression.
By comparing redundant enhancers to single enhancers (enhancers present in a single copy in a gene locus), we observed that the DNA sequence encryption differs between these two classes of enhancers, suggesting a difference in their regulatory mechanisms. Initiator enhancers, which are a subset of redundant enhancers and show similar sequence encryption to single enhancers, differ from the rest of redundant enhancers in their sequence encryption, evolutionary conservation and proximity to target genes. Genes hosting initiator enhancers in their loci feature elevated levels of expression. Initiator enhancers show a high level of 3D chromatin contacts with both transcription start sites and regular enhancers, suggesting their roles as primary activators and intermediate catalysts of gene expression, through which the regulatory signals of redundant enhancers are propagated to the target genes. In addition, GWAS and eQTLs variants are significantly enriched in initiator enhancers compared to redundant enhancers, suggesting a key functional role these sequences play in gene regulation.
The specific characteristics and widespread abundance of initiator enhancers advocate for a possible universal hierarchical mechanism of tissue-specific gene regulation involving multiple redundant enhancers acting through initiator enhancers.
基因座的调控景观通常由几个功能冗余的增强子组成，这些增强子为其调控程序建立了表型稳健性和进化稳定性。然而，目前尚不清楚冗余增强子采用何种机制来协同调控基因表达。
通过比较冗余增强子和单一增强子（在基因座中仅存在一个拷贝的增强子），我们观察到这两类增强子的 DNA 序列加密方式存在差异，这表明它们的调控机制存在差异。启动子增强子是冗余增强子的一个子集，与单一增强子具有相似的序列加密方式，与其他冗余增强子在序列加密、进化保守性和与靶基因的接近程度上存在差异。在其基因座中具有启动子增强子的基因表现出更高水平的表达。启动子增强子与转录起始位点和常规增强子之间具有高水平的 3D 染色质接触，表明它们作为基因表达的主要激活子和中间催化剂的作用，通过这种作用，冗余增强子的调控信号被传递到靶基因。此外，与冗余增强子相比，GWAS 和 eQTLs 变体在启动子增强子中显著富集，这表明这些序列在基因调控中发挥着关键的功能作用。
启动子增强子的特定特征和广泛存在表明，涉及多个冗余增强子通过启动子增强子作用的组织特异性基因调控可能存在普遍的分层机制。
