Expression of the myodystrophic R453W mutation of lamin A in C2C12 myoblasts causes promoter-specific and global epigenetic defects.

Abstract

Autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) is characterized by muscle wasting and is caused by mutations in the LMNA gene encoding A-type lamins. Overexpression of the EDMD lamin A R453W mutation in C2C12 myoblasts impairs myogenic differentiation. We show here the influence of stable expression of the R453W and of the Dunnigan-type partial lipodystrophy R482W mutation of lamin A in C2C12 cells on transcription and epigenetic regulation of the myogenin (Myog) gene and on global chromatin organization. Expression of R453W-, but not R482W-lamin A, impairs activation of Myog and maintains a repressive chromatin state on the Myog promoter upon induction of differentiation, marked by H3 lysine (K) 9 dimethylation and failure to hypertrimethylate H3K4. Cells expressing WT-LaA also fail to hypertrimethylate H3K4. No defect occurs at the level of Myog promoter DNA methylation in any of the clones. Expression of R453W-lamin A and to a lesser extent R482W-lamin A in undifferentiated C2C12 cells redistributes H3K9me3 from pericentric heterochromatin. R453W-lamin A also elicits a redistribution of H3K27me3 from inactive X (Xi) and partial decondensation of Xi, but maintains Xist expression and coating of Xi, indicating that Xi remains inactivated. Our results argue that gene-specific and genome-wide chromatin rearrangements may constitute a molecular basis for laminopathies.

• Authors: Anne-Mari Håkelien, Erwan Delbarre, Kristine G Gaustad, Brigitte Buendia, Philippe Collas
• Journal: Experimental cell research (Exp Cell Res) Vol. 314 Issue 8 Pg. 1869-80 (May 01 2008) ISSN: 0014-4827 [Print] United States
• PMID: 18396274 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histones
• LMNA protein, human
• Lamin Type A
• Myogenin
• Tryptophan
• Arginine

Topics

• Amino Acid Substitution
• Animals
• Arginine (genetics)
• Cell Differentiation
• Cell Line
• Cell Nucleus (enzymology)
• DNA Methylation
• Epigenesis, Genetic
• Histones (chemistry, metabolism)
• Humans
• Lamin Type A (genetics, metabolism)
• Methylation
• Mice
• Muscular Dystrophy, Emery-Dreifuss (genetics)
• Mutation, Missense
• Myoblasts (cytology, metabolism)
• Myogenin (biosynthesis, genetics)
• Promoter Regions, Genetic
• Tryptophan (genetics)
• Up-Regulation
• X Chromosome (enzymology)