Interactions between the genome and the nuclear lamina are multivalent and cooperative.

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.