Loss of an H3K9me anchor rescues laminopathy-linked changes in nuclear organization and muscle function in an Emery-Dreifuss muscular dystrophy model.

Abstract

Mutations in the nuclear structural protein lamin A produce rare, tissue-specific diseases called laminopathies. The introduction of a human Emery-Dreifuss muscular dystrophy (EDMD)-inducing mutation into the C. elegans lamin (LMN-Y59C), recapitulates many muscular dystrophy phenotypes, and correlates with hyper-sequestration of a heterochromatic array at the nuclear periphery in muscle cells. Using muscle-specific emerin Dam-ID in worms, we monitored the effects of the mutation on endogenous chromatin. An increased contact with the nuclear periphery along chromosome arms, and an enhanced release of chromosomal centers, coincided with the disease phenotypes of reduced locomotion and compromised sarcomere integrity. The coupling of the LMN-Y59C mutation with the ablation of CEC-4, a chromodomain protein that anchors H3K9-methylated chromatin at the nuclear envelope (NE), suppressed the muscle-associated disease phenotypes. Deletion of cec-4 also rescued LMN-Y59C-linked alterations in chromatin organization and some changes in transcription. Sequences that changed position in the LMN-Y59C mutant, are enriched for E2F (EFL-2)-binding sites, consistent with previous studies suggesting that altered Rb-E2F interaction with lamin A may contribute to muscle dysfunction. In summary, we were able to counteract the dominant muscle-specific defects provoked by LMNA mutation by the ablation of a lamin-associated H3K9me anchor, suggesting a novel therapeutic pathway for EDMD.

• Authors: Jennifer C Harr, Christoph D Schmid, Celia Muñoz-Jiménez, Raquel Romero-Bueno, Véronique Kalck, Adriana Gonzalez-Sandoval, Michael H Hauer, Jan Padeken, Peter Askjaer, Anna Mattout, Susan M Gasser
• Journal: Genes & development (Genes Dev) Vol. 34 Issue 7-8 Pg. 560-579 (04 01 2020) ISSN: 1549-5477 [Electronic] United States
• PMID: 32139421 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Harr et al.; Published by Cold Spring Harbor Laboratory Press.

Chemical References

• CEC-4 protein, C elegans
• Caenorhabditis elegans Proteins
• Chromatin
• Chromosomal Proteins, Non-Histone
• LMN-1 protein, C elegans
• Laminin

Topics

• Animals
• Binding Sites (genetics)
• Caenorhabditis elegans (genetics, metabolism)
• Caenorhabditis elegans Proteins (genetics, metabolism)
• Cell Nucleus (genetics, pathology)
• Chromatin (genetics)
• Chromosomal Proteins, Non-Histone (genetics)
• Disease Models, Animal
• Gene Deletion
• Genome, Helminth (genetics)
• Laminin (genetics, metabolism)
• Muscles (physiopathology)
• Muscular Dystrophy, Emery-Dreifuss (genetics, physiopathology)
• Mutation
• Protein Structure, Tertiary (genetics)
• Sarcomeres (chemistry, genetics)
• Transcription, Genetic (genetics)