title: Constitutive nuclear lamina-genome interactions are highly conserved and associated with A/T-rich sequence.
abstract: In metazoans, the nuclear lamina is thought to play an important role in the spatial organization of interphase chromosomes, by providing anchoring sites for large genomic segments named lamina-associated domains (LADs). Some of these LADs are cell-type specific, while many others appear constitutively associated with the lamina. Constitutive LADs (cLADs) may contribute to a basal chromosome architecture. By comparison of mouse and human lamina interaction maps, we find that the sizes and genomic positions of cLADs are strongly conserved. Moreover, cLADs are depleted of synteny breakpoints, pointing to evolutionary selective pressure to keep cLADs intact. Paradoxically, the overall sequence conservation is low for cLADs. Instead, cLADs are universally characterized by long stretches of DNA of high A/T content. Cell-type specific LADs also tend to adhere to this "A/T rule" in embryonic stem cells, but not in differentiated cells. This suggests that the A/T rule represents a default positioning mechanism that is locally overruled during lineage commitment. Analysis of paralogs suggests that during evolution changes in A/T content have driven the relocation of genes to and from the nuclear lamina, in tight association with changes in expression level. Taken together, these results reveal that the spatial organization of mammalian genomes is highly conserved and tightly linked to local nucleotide composition.
authors.affiliation: Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: Meuleman
authors.forename: Daan
authors.initials: D
authors.lastname: Peric-Hupkes
authors.forename: Jop
authors.initials: J
authors.lastname: Kind
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Beaudry
authors.forename: Ludo
authors.initials: L
authors.lastname: Pagie
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.forename: Marcel
authors.initials: M
authors.lastname: Reinders
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.forename: Bas
authors.initials: B
authors.lastname: van Steensel
mesh_terms: D020856:AT Rich Sequence; D000818:Animals; D017173:Caenorhabditis elegans; D017124:Conserved Sequence / Q000235:genetics; D004331:Drosophila melanogaster; D053595:Embryonic Stem Cells / Q000378:metabolism; D016678:Genome; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism; D034921:Lamin Type B / Q000378:metabolism; D051379:Mice; D034881:Nuclear Lamina / Q000378:metabolism*; D050811:Octamer Transcription Factor-1 / Q000378:metabolism
chemical_list: D034904:Lamin Type A; D034921:Lamin Type B; D050811:Octamer Transcription Factor-1