Huang Yike, Verstegen Marjon J A M, Tjalsma Sjoerd J D, Krijger Peter H L, Gupta Kavvya, Park Minhee, Boettiger Alistair, de Laat Wouter
Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Center Utrecht, Utrecht 3584 CT, the Netherlands.
Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
Genes Dev. 2025 Mar 3;39(5-6):348-363. doi: 10.1101/gad.352235.124.
Enhancers are tissue-specific regulatory DNA elements that can activate transcription of genes over distance. Their target genes most often are located in the same contact domain-chromosomal entities formed by cohesin DNA loop extrusion and typically flanked by CTCF-bound boundaries. Enhancers shared by multiple unrelated genes are underexplored but may be more common than anticipated. Here, we analyzed the interplay between an enhancer and two distal functionally unrelated genes residing at opposite domain boundaries. The enhancer strongly activated their expression and supported their frequent interactions. Cohesin structured the domain and supported their transcription, but the genes did not rely on each other's transcription or show gene competition. Deleting either domain boundary not only extended the contact domain but led to reduced contacts within the original domain and reduction in the expression of both genes. Conversely, by isolating either gene with the enhancer in shorter domains, through insertion of new CTCF boundaries, intradomain contact frequencies increased, and the gene isolated with the enhancer was upregulated. Collectively, this shows that an enhancer can independently activate unrelated distal genes and that long-range gene regulation benefits from operating in small contact domains.
增强子是组织特异性的调控性DNA元件，可远距离激活基因转录。它们的靶基因通常位于由黏连蛋白介导的DNA环挤压形成的同一接触结构域——染色体实体中，且通常两侧为CTCF结合边界。多个不相关基因共享的增强子尚未得到充分研究，但可能比预期更为常见。在这里，我们分析了一个增强子与位于相反结构域边界的两个远距离功能不相关基因之间的相互作用。该增强子强烈激活它们的表达并支持它们频繁相互作用。黏连蛋白构建了结构域并支持它们的转录，但这些基因并不依赖彼此的转录，也未表现出基因竞争。删除任何一个结构域边界不仅会扩展接触结构域，还会导致原始结构域内的接触减少以及两个基因的表达降低。相反，通过在较短结构域中用增强子隔离任一基因，通过插入新的CTCF边界，结构域内的接触频率增加，与增强子隔离的基因被上调。总的来说，这表明增强子可以独立激活不相关的远距离基因，并且远距离基因调控受益于在小接触结构域中发挥作用。
