title: Mapping of lamin A- and progerin-interacting genome regions.
abstract: Mutations in the A-type lamins A and C, two major components of the nuclear lamina, cause a large group of phenotypically diverse diseases collectively referred to as laminopathies. These conditions often involve defects in chromatin organization. However, it is unclear whether A-type lamins interact with chromatin in vivo and whether aberrant chromatin-lamin interactions contribute to disease. Here, we have used an unbiased approach to comparatively map genome-wide interactions of gene promoters with lamin A and progerin, the mutated lamin A isoform responsible for the premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS) in mouse cardiac myoytes and embryonic fibroblasts. We find that lamin A-associated genes are predominantly transcriptionally silent and that loss of lamin association leads to the relocation of peripherally localized genes, but not necessarily to their activation. We demonstrate that progerin induces global changes in chromatin organization by enhancing interactions with a specific subset of genes in addition to the identified lamin A-associated genes. These observations demonstrate disease-related changes in higher order genome organization in HGPS and provide novel insights into the role of lamin-chromatin interactions in chromatin organization.
authors.affiliation: Genome Cell Biology Group, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Nard
authors.initials: N
authors.lastname: Kubben
authors.forename: Michiel
authors.initials: M
authors.lastname: Adriaens
authors.forename: Wouter
authors.initials: W
authors.lastname: Meuleman
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Voncken
authors.forename: Bas
authors.initials: B
authors.lastname: van Steensel
authors.forename: Tom
authors.initials: T
authors.lastname: Misteli
mesh_terms: D000818:Animals; D002460:Cell Line; D002874:Chromosome Mapping; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D032342:Muscle Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011371:Progeria / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*
chemical_list: D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A