Cohesin forms fountains at active enhancers in C. elegans-猫眼课题宝

DOI：

10.1101/2023.07.14.549011

发表时间：

2023-07

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Bolaji N. Isiaka;J. Semple;Anja Haemmerli;Saurabh Thapliyal;Klement Stojanovski;Moushumi Das;N. Gilbert;Dominique A. Glauser;Benjamin D. Towbin;D. Jost;P. Meister

转录增强子必须有效且特异地找到它们的靶基因。染色质构象捕获技术揭示了拓扑相关结构域（TADs）在哺乳动物染色体三维分割中限制启动子增强子搜索空间的关键作用。在线虫中，尽管已经鉴定了超过30'000个具有特征性增强子染色质特征的序列，但常染色体基因组不被TAD分段，从而提出了指导增强子-启动子特异性的机制的问题。使用高分辨率HiC，我们表明增强子基因座与从增强子延伸10-50 kb的3D发夹样结构相关，下文称为喷泉。喷泉对活性增强子是特异性的，积累主要的体细胞粘附素，当后者在体内被切割时消失。喷泉积累拓扑约束和丰富的拓扑异构酶和负超螺旋DNA粘合剂peptien。短期拓扑异构酶耗竭导致喷泉尖端的小规模结构变化。在功能上，喷泉消失与增强子近端基因激活相关，这表明喷泉起着与TADs相似的作用，并直接增强子-启动子相互作用，特别是对于神经元中表达的基因。我们直接观察到这种细胞类型特异性上调skn-1/Nrf基因在一对头部神经元。从表型上看，粘着蛋白裂解对线虫运动和觅食态度有重大影响，表明神经元基因表达的变化影响神经系统功能，让人联想到人类中由粘着蛋白突变引起的病理。总之，这项研究强调了3D基因组组织在增强子中的粘着蛋白，转录基因调控和动物行为之间的明确联系。

Transcriptional enhancers must find their target genes both efficiently and specifically. Chromatin conformation capture revealed the critical function of three-dimensional chromosome segmentation by topologically associated domains (TADs) to limit the search space of enhancers for promoters in mammals. In nematodes, although more than 30’000 sequences with characteristic enhancer chromatin features have been identified, the autosomal genome is not segmented by TADs, raising the question of the mechanism directing enhancer-promoter specificity. Using high-resolution HiC, we show that enhancer loci correlate with 3D hairpin-like structures extending 10-50 kb from the enhancers, hereafter designated as fountains. Fountains are specific to active enhancers, accumulate the major somatic cohesin and disappear when the latter is cleaved in vivo. Fountains accumulate topological constraints and are enriched for topoisomerases and the negatively-supercoiled DNA binder psoralen. Short-term topoisomerase depletion leads to small-scale structural changes at the fountain tip. Functionally, fountain disappearance correlates with enhancer-proximal gene activation, suggesting fountains play a similar role as TADs and direct enhancer-promoter interactions, in particular for genes expressed in neurons. We directly observe this cell-type specific upregulation for the skn-1/Nrf gene in a pair of head neurons. Phenotypically, cohesin cleavage has a major impact on nematode movement and foraging attitudes, demonstrating that changes in neuronal gene expression impact nervous system function, reminiscent of pathologies caused by cohesin mutations in humans. Together, this study highlights a clear link between 3D genome organization at enhancers by cohesin, transcriptional gene regulation and animal behavior.

Cohesin forms fountains at active enhancers in C. elegans

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