Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions

Proper genome functionality is underpinned by the non-random, spatial or ganisation of chromatin. At the periphery of the nucleus, the association of chr omatin with the nuclear lamina is thought to facilitate both structural organisa tion and regulation of gene expression. Except for a small number of individual loci, the regions of the human genome that locate at the nuclear lamina have not been identified. Here we used DamID to map the interaction sites of lamin B1 at high resolution in human fibroblasts. We show that almost half of the human gen ome preferentially associates with the nuclear lamina. Chromatin-lamina interact ions occur via sharply demarcated domains of up to several megabases in size, wh ich are bordered by similar sized domains that do not associate with the lamina. Lamina associated domains (LADs) are typified by low gene density and low gene expression levels. This is reflected by low levels of PolII binding and histone modification H3K4me2, in combination with enrichment of H3K27me3 (and H3K9?). A considerable subset of LADs is flanked by active promoters pointing outwards, or by the insulator protein CTCF, suggesting possible mechanisms of LAD confinemen t. Finally, we found that chromosome re-arrangements occur more frequently betwe en loci located either within or outside LADs. The identification of enormous, s harply defined stretches of the human genome that associate with the nuclear lam ina provides unprecedented insights into the 3D organisation of chromatin within the nucleus. Our results reveal the division of the human genome into periphera l and internal domains, which is echoed in genome functionality. Keywords: DamID