近日，美国哥伦比亚大学教授Stavros Lomvardas及其研究小组开发出固体相变作为基因组折叠悖论的解决方案。该项研究成果发表在2025年5月14日出版的《自然》上。

为了深入了解这一过程，研究小组在体外用重组蛋白和增强子DNA组装了嗅觉受体（OR）增强子枢纽。增强子中心的无细胞重构表明，OR增强子形成具有非互性、固体样特征的核蛋白凝聚体。这些固体凝聚体的组装是由富含OR增强子的特定DNA基序精心安排的，这些基序可能赋予其驻留的LHX2-EBF1-LDB1复合物独特的同型特性。体内单分子跟踪和脉冲追踪实验证实，在生理蛋白浓度下，LHX2和EBF1在OSN核中组装具有OR转录能力的凝聚体，具有固体性质。因此，受DNA序列影响的亲同性核蛋白相互作用产生了新型的生物分子凝聚，这可能为跨细胞类型的远程基因组接触的稳定性和特异性提供了一种可推广的解释。

研究人员表示，超远程基因组接触是神经元基因组结构的关键组成部分，构成了一个生化谜。这是因为主旋律调控DNA元件与位于数百个碱基之外的DNA序列进行选择性和稳定的接触，而不是与由完全相同的转录因子占据的近端序列相互作用。这在嗅觉感觉神经元（OSNs）中得到了例证，其中只有一小部分LHX2-EBF1-LDB1结合位点相互作用，聚集成高度选择性的多染色体增强子中心。

附：英文原文

Title: Solid phase transitions as a solution to the genome folding paradox

Author: Pulupa, Joan, McArthur, Natalie G., Stathi, Olga, Wang, Miao, Zazhytska, Marianna, Pirozzolo, Isabella D., Nayar, Ahana, Shapiro, Lawrence, Lomvardas, Stavros

Issue&Volume: 2025-05-14

Abstract: Ultra-long-range genomic contacts, which are key components of neuronal genome architecture1,2,3, constitute a biochemical enigma. This is because regulatory DNA elements make selective and stable contacts with DNA sequences located hundreds of kilobases away, instead of interacting with proximal sequences occupied by the exact same transcription factors1,4. This is exemplified in olfactory sensory neurons (OSNs), in which only a fraction of LHX2-, EBF1- and LDB1-bound sites interact with each other, converging into highly selective multi-chromosomal enhancer hubs5. To obtain biochemical insight into this process, here we assembled olfactory receptor (OR) enhancer hubs in vitro with recombinant proteins and enhancer DNA. Cell-free reconstitution of enhancer hubs revealed that OR enhancers form nucleoprotein condensates with unusual, solid-like characteristics. Assembly of these solid condensates is orchestrated by specific DNA motifs enriched in OR enhancers, which are likely to confer distinct homotypic properties on their resident LHX2–EBF1–LDB1 complexes. Single-molecule tracking and pulse-chase experiments in vivo confirmed that LHX2 and EBF1 assemble OR-transcription-competent condensates with solid properties in OSN nuclei, under physiological concentrations of protein. Thus, homophilic nucleoprotein interactions that are influenced by DNA sequence generate new types of biomolecular condensate, which might provide a generalizable explanation for the stability and specificity of long-range genomic contacts across cell types.

DOI: 10.1038/s41586-025-09043-6

Source: https://www.nature.com/articles/s41586-025-09043-6