Department of Pediatrics, The University of Chicago, Chicago, IL 60637, USA; Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA; Department of Biology, Lunds University, Lund 22362, Sweden.
Dev Cell. 2020 Mar 23;52(6):699-713.e11. doi: 10.1016/j.devcel.2020.02.011.
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.
LMNA 编码核层粘连蛋白 A/C，将核层粘连蛋白相关结构域 (LAD) 固定在核周。LMNA 突变会导致退行性疾病，包括早老症亨廷顿病，但发病机制尚不清楚。我们报告称，在整个细胞周期中，人成纤维细胞中的 Ser22 磷酸化 (pS22) 层粘连蛋白 A/C 定位于核内部。pS22-层粘连蛋白 A/C 与转录激活因子 c-Jun 共同结合的一组假定的活性增强子而非 LAD 相互作用。在早老症患者的成纤维细胞中，一部分 pS22-层粘连蛋白 A/C 结合位点丢失，而在正常静止的位点出现新的 pS22-层粘连蛋白 A/C 结合位点。新的 pS22-层粘连蛋白 A/C 结合伴随着组蛋白乙酰化增加、c-Jun 结合增加以及与早老症病理生理学相关的附近基因的上调。这些结果表明，层粘连蛋白 A/C 通过增强子结合来调节基因表达。层粘连蛋白 A/C 的基因调控功能（而非 LAD 固定功能）的破坏可能是由 LMNA 突变引起的疾病的发病机制的基础。
