小柯机器人

美国国立卫生研究院Pedro P. Rocha课题组发现，增强子与启动子的相互作用可以绕过CTCF介导的边界，并有助于表型的稳健性。相关论文于2023年1月30日在线发表于国际学术期刊《自然—遗传学》。

研究人员表示，增强子如何激活其远端靶标启动子仍不完全清楚。

研究人员剖析了CTCF介导的环化如何促进和限制这种调控相互作用。通过利用小鼠突变体的一个等位基因系列，研究人员表明CTCF既不是Sox2基因与远端增强子相互作用所需的，也不是其表达所需的。在Sox2及其远端增强子之间插入CTCF基序的各种组合产生了具有不同绝缘程度的边界，这与转录输出的减少直接相关。然而，在外胚层和神经组织中，增强子接触和转录诱导都不能完全消除，并且插入也不能破坏着床和神经发生。

相比之下，在携带最强边界的突变体前部前肠中检测不到Sox2的表达，这些动物在该组织中完全表型地丢失了Sox2。研究人员认为具有高密度调控活性的增强子簇可以更好地克服物理障碍，以保持忠实的基因表达和表型一致性。

附：英文原文

Title: Enhancer–promoter interactions can bypass CTCF-mediated boundaries and contribute to phenotypic robustness

Author: Chakraborty, Shreeta, Kopitchinski, Nina, Zuo, Zhenyu, Eraso, Ariel, Awasthi, Parirokh, Chari, Raj, Mitra, Apratim, Tobias, Ian C., Moorthy, Sakthi D., Dale, Ryan K., Mitchell, Jennifer A., Petros, Timothy J., Rocha, Pedro P.

Issue&Volume: 2023-01-30

Abstract: How enhancers activate their distal target promoters remains incompletely understood. Here we dissect how CTCF-mediated loops facilitate and restrict such regulatory interactions. Using an allelic series of mouse mutants, we show that CTCF is neither required for the interaction of the Sox2 gene with distal enhancers, nor for its expression. Insertion of various combinations of CTCF motifs, between Sox2 and its distal enhancers, generated boundaries with varying degrees of insulation that directly correlated with reduced transcriptional output. However, in both epiblast and neural tissues, enhancer contacts and transcriptional induction could not be fully abolished, and insertions failed to disrupt implantation and neurogenesis. In contrast, Sox2 expression was undetectable in the anterior foregut of mutants carrying the strongest boundaries, and these animals fully phenocopied loss of SOX2 in this tissue. We propose that enhancer clusters with a high density of regulatory activity can better overcome physical barriers to maintain faithful gene expression and phenotypic robustness.

DOI: 10.1038/s41588-022-01295-6

Source: https://www.nature.com/articles/s41588-022-01295-6

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