title: Altered chromosomal positioning, compaction, and gene expression with a lamin A/C gene mutation.
abstract: BACKGROUND
  Lamins A and C, encoded by the LMNA gene, are filamentous proteins that form the core scaffold of the nuclear lamina. Dominant LMNA gene mutations cause multiple human diseases including cardiac and skeletal myopathies. The nuclear lamina is thought to regulate gene expression by its direct interaction with chromatin. LMNA gene mutations may mediate disease by disrupting normal gene expression.
  
  
  RESULTS
  To investigate the hypothesis that mutant lamin A/C changes the lamina's ability to interact with chromatin, we studied gene misexpression resulting from the cardiomyopathic LMNA E161K mutation and correlated this with changes in chromosome positioning. We identified clusters of misexpressed genes and examined the nuclear positioning of two such genomic clusters, each harboring genes relevant to striated muscle disease including LMO7 and MBNL2. Both gene clusters were found to be more centrally positioned in LMNA-mutant nuclei. Additionally, these loci were less compacted. In LMNA mutant heart and fibroblasts, we found that chromosome 13 had a disproportionately high fraction of misexpressed genes. Using three-dimensional fluorescence in situ hybridization we found that the entire territory of chromosome 13 was displaced towards the center of the nucleus in LMNA mutant fibroblasts. Additional cardiomyopathic LMNA gene mutations were also shown to have abnormal positioning of chromosome 13, although in the opposite direction.
  
  
  CONCLUSIONS
  These data support a model in which LMNA mutations perturb the intranuclear positioning and compaction of chromosomal domains and provide a mechanism by which gene expression may be altered.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Mewborn
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Puckelwartz
authors.forename: Fida
authors.initials: F
authors.lastname: Abuisneineh
authors.forename: John P
authors.initials: JP
authors.lastname: Fahrenbach
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Heather
authors.initials: H
authors.lastname: MacLeod
authors.forename: Lisa
authors.initials: L
authors.lastname: Dellefave
authors.forename: Peter
authors.initials: P
authors.lastname: Pytel
authors.forename: Sara
authors.initials: S
authors.lastname: Selig
authors.forename: Christine M
authors.initials: CM
authors.lastname: Labno
authors.forename: Karen
authors.initials: K
authors.lastname: Reddy
authors.forename: Harinder
authors.initials: H
authors.lastname: Singh
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McNally
mesh_terms: D000328:Adult; D009202:Cardiomyopathies / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002874:Chromosome Mapping; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods; D009154:Mutation; D009206:Myocardium / Q000378:metabolism
chemical_list: D034904:Lamin Type A; C440308:lamin C