Altered chromosomal positioning, Compaction, and gene expression with a lamin A/C gene mutation

Stephanie K. Mewborn, Megan J. Puckelwartz, Fida Abuisneineh, John P. Fahrenbach, Yuan Zhang, Heather MacLeod, Lisa Dellefave, Peter Pytel, Sara Selig, Christine M. Labno, Karen L Reddy, Harinder Singh, Elizabeth McNally

Research output: Contribution to journalArticle

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. Methods/Findings: 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.

Original languageEnglish (US)
Article numbere14342
JournalPLoS One
Volume5
Issue number12
DOIs
StatePublished - 2010

Fingerprint

Lamin Type A
Gene expression
Compaction
Chromosomes, Human, Pair 13
Genes
mutation
Gene Expression
gene expression
Mutation
Nuclear Lamina
laminae (animals)
Chromosomes
chromosomes
mutants
Multigene Family
genes
muscular diseases
Chromatin
Chromosome Positioning
multigene family

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mewborn, S. K., Puckelwartz, M. J., Abuisneineh, F., Fahrenbach, J. P., Zhang, Y., MacLeod, H., ... McNally, E. (2010). Altered chromosomal positioning, Compaction, and gene expression with a lamin A/C gene mutation. PLoS One, 5(12), [e14342]. https://doi.org/10.1371/journal.pone.0014342

Altered chromosomal positioning, Compaction, and gene expression with a lamin A/C gene mutation. / Mewborn, Stephanie K.; Puckelwartz, Megan J.; Abuisneineh, Fida; Fahrenbach, John P.; Zhang, Yuan; MacLeod, Heather; Dellefave, Lisa; Pytel, Peter; Selig, Sara; Labno, Christine M.; Reddy, Karen L; Singh, Harinder; McNally, Elizabeth.

In: PLoS One, Vol. 5, No. 12, e14342, 2010.

Research output: Contribution to journalArticle

Mewborn, SK, Puckelwartz, MJ, Abuisneineh, F, Fahrenbach, JP, Zhang, Y, MacLeod, H, Dellefave, L, Pytel, P, Selig, S, Labno, CM, Reddy, KL, Singh, H & McNally, E 2010, 'Altered chromosomal positioning, Compaction, and gene expression with a lamin A/C gene mutation', PLoS One, vol. 5, no. 12, e14342. https://doi.org/10.1371/journal.pone.0014342
Mewborn SK, Puckelwartz MJ, Abuisneineh F, Fahrenbach JP, Zhang Y, MacLeod H et al. Altered chromosomal positioning, Compaction, and gene expression with a lamin A/C gene mutation. PLoS One. 2010;5(12). e14342. https://doi.org/10.1371/journal.pone.0014342
Mewborn, Stephanie K. ; Puckelwartz, Megan J. ; Abuisneineh, Fida ; Fahrenbach, John P. ; Zhang, Yuan ; MacLeod, Heather ; Dellefave, Lisa ; Pytel, Peter ; Selig, Sara ; Labno, Christine M. ; Reddy, Karen L ; Singh, Harinder ; McNally, Elizabeth. / Altered chromosomal positioning, Compaction, and gene expression with a lamin A/C gene mutation. In: PLoS One. 2010 ; Vol. 5, No. 12.
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