Lamins form a proteinaceous meshwork as a major structural component of the nucleus. Lamins, along with their interactors, act as determinants for chromatin organization throughout the nucleus. The major dominant missense mutations responsible for autosomal dominant forms of muscular dystrophies reside in the Ig fold domain of lamin A. However, how lamin A contributes to the distribution of heterochromatin and balances euchromatin, and how it relocates epigenetic marks to shape chromatin states, remains poorly defined, making it difficult to draw conclusions about the prognosis of lamin A-mediated muscular dystrophies. In the first part of this report, we identified the in vitro organization of full-length lamin A proteins due to two well-documented Ig LMNA mutations, R453W and W514R. We further demonstrated that both lamin A/C mutant cells predominantly expressed nucleoplasmic aggregates. Labeling specific markers of epigenetics allowed correlation of lamin A mutations with epigenetic mechanisms. In addition to manipulating epigenetic mechanisms, our proteomic studies traced diverse expressions of transcription regulators, RNA synthesis and processing proteins, protein translation components, and posttranslational modifications. These data suggest severe perturbations in targeting other proteins to the nucleus.

中文翻译：

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研究肌营养不良症 lamin A Ig fold 结构域突变体的差异结构组织和基因表达调控网络。


核纤层蛋白形成蛋白质网状结构，作为细胞核的主要结构成分。核纤层蛋白及其相互作用物是整个细胞核染色质组织的决定因素。导致肌营养不良常染色体显性遗传的主要显性错义突变位于核纤层蛋白 A 的 Ig 折叠结构域。然而，层粘连蛋白 A 如何促进异染色质的分布和平衡常染色质，以及它如何重新定位表观遗传标记以形成染色质状态，仍然不清楚，因此很难得出关于层粘连蛋白 A 介导的肌营养不良症的预后的结论。在本报告的第一部分，我们确定了由于两种有据可查的 Ig LMNA 突变 R453W 和 W514R 而导致的全长核纤层蛋白的体外组织。我们进一步证明，两种核纤层蛋白 A/C 突变细胞都主要表达核质聚集体。标记表观遗传学的特异性标志物允许层粘连蛋白 A 突变与表观遗传机制的相关性。除了操纵表观遗传机制外，我们的蛋白质组学研究还追踪了转录调节因子、RNA 合成和加工蛋白质、蛋白质翻译成分和翻译后修饰的不同表达。这些数据表明，将其他蛋白质靶向细胞核时存在严重扰动。