Dauban Lise, Eder Mathias, de Haas Marcel, Franceschini-Santos Vinícius H, Yañez-Cuna J Omar, Martinovic Moreno, van Schaik Tom, Leemans Christ, Teunissen Hans, Rademaker Koen, Martinez Ara Miguel, Verkuilen Martijn, de Wit Elzo, van Steensel Bas
Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Division of Molecular Genetics and Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Nat Struct Mol Biol. 2025 Sep 1. doi: 10.1038/s41594-025-01655-w.
Lamina-associated domains (LADs) are megabase-sized genomic regions that interact with the nuclear lamina (NL). It is not yet understood how their interactions with the NL are encoded in their DNA. Here we designed an efficient LAD 'scrambling' approach, based on transposon-mediated local hopping of loxP recombination sites, to generate series of large deletions and inversions that span LADs and flanking sequences. Mapping of NL interactions in these rearrangements revealed that, in mouse embryonic stem cells, a single LAD contacts the NL through multiple regions that act cooperatively or redundantly; some have more affinity for the NL than others and can pull neighboring sequences to the NL. Genes drawn toward the NL showed often but not always reduced expression and increased H3K9me3 levels. Furthermore, neighboring LADs can cooperatively interact with the NL when placed close enough to each other. These results elucidate principles that govern the positioning of megabase-sized genomic regions inside the cell nucleus.
核纤层相关结构域（LADs）是与核纤层（NL）相互作用的兆碱基大小的基因组区域。目前尚不清楚它们与核纤层的相互作用是如何在其DNA中编码的。在这里，我们设计了一种高效的LAD“重排”方法，基于转座子介导的loxP重组位点局部跳跃，以产生一系列跨越LAD及其侧翼序列的大缺失和倒位。对这些重排中核纤层相互作用的定位揭示，在小鼠胚胎干细胞中，单个LAD通过多个协同或冗余作用的区域与核纤层接触；其中一些对核纤层的亲和力比其他区域更高，并且可以将相邻序列拉向核纤层。被拉向核纤层的基因通常但并非总是表达降低且H3K9me3水平升高。此外，相邻的LAD在彼此放置足够接近时可以与核纤层协同相互作用。这些结果阐明了控制兆碱基大小的基因组区域在细胞核内定位的原则。
