Genome - nuclear lamina interactions 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 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 neighbouring sequences to the NL. Genes drawn towards the NL showed often, but not always, reduced expression and increased H3K9me3 levels. Furthermore, neighbouring 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. HighlightsO_LIEfficient generation of LAD rearrangements by transposon hopping of loxP elements. C_LIO_LINL interactions are multivalent, with some subregions being more potent tethers than others. C_LIO_LILADs can cooperate to promote their association to the NL. C_LIO_LIChanges in NL association are often accompanied by changes in gene activity and H3K9me3. C_LI