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.

中文翻译：

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在 Emery-Dreifuss 肌营养不良症模型中，H3K9me 锚的缺失挽救了核组织和肌肉功能中与椎板病相关的变化。

核结构蛋白核纤层蛋白 A 的突变会产生罕见的组织特异性疾病，称为核纤层蛋白病。将人类 Emery-Dreifuss 肌营养不良症 (EDMD) 诱导突变引入线虫核纤层蛋白 (LMN-Y59C) 概括了许多肌营养不良症的表型，并与肌肉细胞核周围异染色质阵列的过度隔离相关。在蠕虫中使用肌肉特异性 emerin Dam-ID，我们监测了突变对内源染色质的影响。沿染色体臂与核外围的接触增加，染色体中心的释放增加，与运动减少和肌节完整性受损的疾病表型一致。LMN-Y59C 突变与 CEC-4 消融的结合，CEC-4 是一种将 H3K9 甲基化染色质锚定在核膜 (NE) 的染色域蛋白，抑制了肌肉相关疾病表型。删除cec-4还挽救了 LMN-Y59C 相关的染色质组织改变和转录的一些变化。在 LMN-Y59C 突变体中改变位置的序列富含 E2F (EFL-2) 结合位点，这与之前的研究一致，表明改变的 Rb-E2F 与核纤层蛋白 A 的相互作用可能导致肌肉功能障碍。总之，我们能够通过消融核纤层蛋白相关的 H3K9me 锚来抵消 LMNA 突变引起的显性肌肉特异性缺陷，这表明 EDMD 的新治疗途径。