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Gene expression, chromosome position and lamin A/C mutations

机译：基因表达，染色体位置和lamin A / C突变

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The nuclear lamina is increasingly being appreciated for its epigenetic role in regulating gene expression. The nuclear lamina underlies the inner nuclear membrane and, in post mitotic cells, is composed of a latticework primarily formed by the intermediate filament protein, lamin A/C. Although not well defined, lamin-associated domains have been described, and these domains are determined by DNA sequence and chromatin conformation. Lamin-associated domains are positioned to mediate the interaction with the nuclear membrane, where they contribute to transcriptional regulation. Although lamin-associated domains are primarily considered to be repressive in nature, those nearer to nuclear pores may actually promote tran-scription. Mutations in LMNA, the gene encoding lamins A and C, are a relatively common cause of inherited cardiomyopa-thy. As substantial data supports a role for the lamina in its interaction with chromatin and gene regulation, we examined the role of a genetically disrupted lamina and the consequences thereof. A dominant LMNA mutation, E161K, that causes inherited cardiomyopathy was studied. Gene expression changes were profiled in a human cardiomyopathic E161K heart, and it was found that chromosome 13 had a high percentage of misexpressed genes. Chromosome 13 was also found to be less tightly associated with the nuclear membrane in E161K mutant cells, thereby linking abnormal gene expres-sion and intranuclear position. These and other studies support a role for the nuclear membrane as an active regulator of gene expression and provide additional support that disrupting this regulation is a mechanism of human disease.
机译：核薄层因其在调节基因表达中的表观遗传学作用而受到越来越多的赞赏。核层位于内核膜之下，在有丝分裂后细胞中，由主要由中间丝蛋白lamin A / C形成的晶格组成。尽管没有很好地定义，但已经描述了层粘连蛋白相关的结构域，并且这些结构域由DNA序列和染色质构象确定。层粘连蛋白相关的结构域被定位为介导与核膜的相互作用，并在其中促进转录调控。尽管主要考虑到与lamin相关的域在本质上是抑制性的，但更靠近核孔的域实际上可能促进转录。编码核纤层蛋白A和C的基因LMNA中的突变是遗传性心肌病的相对常见原因。由于大量数据支持了叶片在与染色质相互作用和基因调控中的作用，因此我们研究了基因破坏的叶片的作用及其后果。研究了导致遗传性心肌病的主要LMNA突变E161K。在人类心肌病性E161K心脏中分析了基因表达的变化，发现13号染色体的错表达基因比例很高。还发现13号染色体与E161K突变细胞中的核膜紧密相关，从而将异常的基因表达与核内位置联系起来。这些研究和其他研究支持了核膜作为基因表达的活性调节剂的作用，并提供了其他支持，即破坏这种调节作用是人类疾病的一种机制。

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