背景:顺式调节元件(CREs)对于调节基因表达至关重要,和G-四链体(G4s),作为原型的非规范DNA结构,可能在这一规定中发挥作用。然而,G4s和CREs之间的关系,尤其是非启动子样功能元件,需要进一步系统的调查。我们旨在调查从DNA元素百科全书(ENCODE)数据推断的G4s与人类cCREs(候选CREs)之间的关联。
结果:我们发现G4s在大多数类型的cCRE中都有显著的丰富,尤其是那些具有类似启动子的签名(PLS)。CTCF信号与H3K4me3或H3K27ac信号的同时出现增强了cCREs和G4s之间的关联。G4s的遗传变异,特别是在他们的G-run中,与cCREs相比,表现出更高的调节潜力和有害作用。与cCREs中的G运行相比,G4s中转录起始位点(TSS)附近的G运行在进化上受到更多限制,而那些远离TSS的相对不太保守。G4s的存在通常与更有利的局部染色质环境有关,以激活和执行cCREs的调节功能,可能归因于G4二级结构的形成。最后,我们发现G4相关cCRE在多种癌症中表现出广泛的激活。
结论:我们的研究表明,G4s是人类顺式调节元件的组成部分,超出了他们在推动者中的潜在作用。G4一级序列与CREs的定位相关,而G4结构与这些元件的激活有关。因此,我们建议将G4s定义为人类基因组中的关键调控元件。
BACKGROUND: Cis-regulatory elements (CREs) are crucial for regulating gene expression, and G-quadruplexes (G4s), as prototypal non-canonical DNA structures, may play a role in this regulation. However, the relationship between G4s and CREs, especially with non-promoter-like functional elements, requires further systematic investigation. We aimed to investigate the associations between G4s and human cCREs (candidate CREs) inferred from the Encyclopedia of DNA Elements (ENCODE) data.
RESULTS: We found that G4s are prominently enriched in most types of cCREs, especially those with promoter-like signatures (PLS). The co-occurrence of CTCF signals with H3K4me3 or H3K27ac signals strengthens the association between cCREs and G4s. Genetic variants in G4s, particularly within their G-runs, exhibit higher regulatory potential and deleterious effects compared to cCREs. The G-runs within G4s near transcriptional start sites (TSSs) are more evolutionarily constrained compared to G-runs in cCREs, while those far from the TSS are relatively less conserved. The presence of G4s is often linked to a more favorable local chromatin environment for the activation and execution of regulatory function of cCREs, potentially attributable to the formation of G4 secondary structures. Finally, we discovered that G4-associated cCREs exhibit widespread activation in a variety of cancers.
CONCLUSIONS: Our study suggests that G4s are integral components of human cis-regulatory elements, extending beyond their potential role in promoters. The G4 primary sequences are associated with the localization of CREs, while the G4 structures are linked to the activation of these elements. Therefore, we propose defining G4s as pivotal regulatory elements in the human genome.