ChIP-seq reported in "Phosphorylated Lamin A/C in the nuclear interior binds active enhancers associated with abnormal transcription in progeria"

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 presents a novel mechanism for disorders caused by LMNA mutations.

LMNA基因编码核纤层蛋白A/C（nuclear Lamin A/C），该蛋白可将核纤层结合结构域（lamina-associated domains, LADs）锚定至核膜外周。LMNA的突变会引发多种退行性疾病，包括早发性衰老疾病哈钦森-吉尔福德早衰综合征（Hutchinson-Gilford progeria），但其具体致病机制至今不明。本研究发现，丝氨酸22位点磷酸化的核纤层蛋白A/C（Ser22-phosphorylated (pS22) Lamin A/C）在人类成纤维细胞的整个细胞周期中均定位于细胞核内部。pS22-核纤层蛋白A/C并不结合LADs，而是与一类推定的活性增强子发生相互作用，其结合位点恰好与转录激活因子c-Jun的共同结合区域重合。在早衰症患者的成纤维细胞中，一部分pS22-核纤层蛋白A/C的结合位点出现丢失，同时在原本处于静息状态的基因座上新增了pS22-核纤层蛋白A/C的结合位点。新增的pS22-核纤层蛋白A/C结合区域伴随有组蛋白乙酰化水平升高、c-Jun结合增强，以及与早衰症病理生理学相关的邻近基因表达上调。上述结果提示，核纤层蛋白A/C可通过结合增强子来调控基因表达。相较于其LAD锚定功能，LMNA突变对该蛋白基因调控功能的破坏，是引发LMNA相关疾病的全新致病机制。