Laboratoire d'Optique et Biosciences (LOB), Ecole Polytechnique, CNRS, INSERM, Institut Polytechnique de Paris, 91120, Palaiseau, France.
State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
BMC Biol. 2024 Aug 26;22(1):177. doi: 10.1186/s12915-024-01971-5.
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.
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.
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.
顺式调控元件（CREs）对于基因表达的调控至关重要，而 G-四链体（G4s）作为典型的非 canonical DNA 结构，可能在这种调控中发挥作用。然而，G4s 与 CREs 之间的关系，尤其是与非启动子样功能元件的关系，需要进一步系统的研究。我们旨在研究从 ENCODE 数据推断出的人类 cCREs（候选 CREs）与 G4s 之间的关联。
我们发现 G4s 高度富集在大多数类型的 cCREs 中，特别是那些具有启动子样特征（PLS）的 cCREs。CTCF 信号与 H3K4me3 或 H3K27ac 信号的共发生增强了 cCREs 与 G4s 之间的关联。G4s 中的遗传变异，特别是其 G- 序列中的遗传变异，与 cCREs 相比，具有更高的调控潜力和有害影响。位于转录起始位点（TSS）附近的 G4s 中的 G- 序列比 cCREs 中的 G- 序列进化上受到更多的限制，而远离 TSS 的 G- 序列则相对不太保守。G4s 的存在通常与 cCREs 激活和执行调节功能的更有利的局部染色质环境相关联，这可能归因于 G4 二级结构的形成。最后，我们发现 G4 相关的 cCREs 在多种癌症中广泛激活。
我们的研究表明，G4s 是人类顺式调控元件的组成部分，超出了它们在启动子中的潜在作用。G4 序列与 CREs 的定位有关，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节元件。
