LMNA encodes nuclear Lamin A/C that tethers lamina-associated domains (LADs) to the nuclear periphery. Mutations in LMNA cause degenerative disorders including the premature aging disorder Hutchinson-Gilford progeria, but the mechanisms are unknown. We report that Ser22-phosphorylated (pS22) Lamin A/C was localized to the nuclear interior in human fibroblasts throughout the cell cycle. pS22-Lamin A/C interacted with a subset of putative active enhancers, not LADs, at locations co-bound by the transcriptional activator c-Jun. In progeria-patient fibroblasts, a subset of pS22-Lamin A/C-binding sites were lost, whereas new pS22-Lamin A/C-binding sites emerged in normally quiescent loci. New pS22-Lamin A/C binding was accompanied by increased histone acetylation, increased c-Jun binding, and upregulation of nearby genes implicated in progeria pathophysiology. These results suggest that Lamin A/C regulates gene expression by enhancer binding. Disruption of the gene regulatory rather than LAD tethering function of Lamin A/C may underlie the pathogenesis of disorders caused by LMNA mutations.

中文翻译：

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核内部的磷酸化Lamin A / C与早衰中异常转录相关的活性增强剂结合。

LMNA编码核纤层蛋白A / C，将核纤层相关域（LAD）束缚到核外围。LMNA的突变会引起变性疾病，包括早衰症Hutchinson-Gilford早衰，但机制尚不清楚。我们报告说，整个细胞周期中，Ser22磷酸化（pS22）Lamin A / C定位于人类成纤维细胞的核内部。pS22-Lamin A / C在转录激活因子c-Jun共同结合的位置与假定的活性增强子而非LAD相互作用。在早衰患者的成纤维细胞中，一部分pS22-Lamin A / C结合位点丢失，而新的pS22-Lamin A / C结合位点出现在正常的静止基因座中。新的pS22-Lamin A / C结合伴随有组蛋白乙酰化增加，c-Jun结合增加，和与早衰症病理生理有关的附近基因的上调。这些结果表明Lamin A / C通过增强子结合调节基因表达。Lamin A / C的基因调节功能而非LAD束缚功能的破坏可能是由LMNA突变引起的疾病的发病机制的基础。