Institute of Medical Pathology, Università Cattolica, Rome 00168, Italy.
Institute of Cell Biology and Neurobiology, National Research Council, Rome 00143, Italy.
Cardiovasc Res. 2016 Nov 1;112(2):555-567. doi: 10.1093/cvr/cvw204.
Beyond the control of nuclear-cytoplasmic trafficking nucleoporins regulate gene expression and are involved in cardiac diseases. Notably, a number of cardiovascular disorders have been linked to alterations in epigenetic mechanisms. Here we aimed to determine the contribution of Nup153 to the epigenetic alterations occurring in cardiomyopathy of dystrophin-deficient mdx mice (C57BL/10ScSn-Dmd mdx /J).
Nup153 was lysine-acetylated and its expression was significantly increased at protein level in mdx hearts compared with controls. Accordingly, lysine acetyl transferase (KAT) activity associated with Nup153 was higher in mdx hearts paralleling increased binding with the lysine acetylases P300/CBP-associated factor (PCAF) and p300. Interestingly, Nup153 silencing in mdx organotypic heart tissue slices caused a reduction in PCAF- and p300-specific activities. Remarkably, the level of nitric oxide (NO), which is reduced in mdx mice, was important for KAT-dependent regulation of Nup153. In fact, treatment of mdx heart tissue with an NO donor or the KAT inhibitor anacardic acid normalized Nup153 protein expression. Nup153 was recruited to chromatin and regulated the transcription of genes involved in cardiac remodelling, including the actin-binding protein nexilin. Accordingly, nexilin protein expression was abrogated by Nup153 silencing in mdx organotypic cultures. Electrophysiological and molecular experiments revealed that Nup153 overexpression in normal cardiomyocytes increases Ca v 1.2 calcium channel expression and function. Alterations in Nup153 protein expression and intracellular localization were also found in dystrophic cardiomyocytes derived from patient-specific induced pluripotent stem cells. Importantly, Nup153 up-regulation and increased acetylation were also found in the heart of Duchenne muscular dystrophy patients.
Our data indicate that Nup153 is an epigenetic regulator which, upon altered NO signalling, mediates the activation of genes potentially associated with early dystrophic cardiac remodelling.
核质转运的核孔蛋白除了对其进行调控外，还参与了基因表达，并与心脏疾病有关。值得注意的是，许多心血管疾病都与表观遗传机制的改变有关。在这里，我们旨在确定 Nup153 在肌营养不良症缺失型 mdx 小鼠（C57BL/10ScSn-Dmd mdx /J）心肌病中发生的表观遗传改变中的作用。
与对照组相比，mdx 心脏中的 Nup153 赖氨酸乙酰化，其蛋白水平显著增加。相应地，mdx 心脏中的 Nup153 相关赖氨酸乙酰转移酶 (KAT) 活性更高，与赖氨酸乙酰转移酶 P300/CBP 相关因子 (PCAF) 和 p300 的结合也更高。有趣的是，mdx 器官心脏组织切片中的 Nup153 沉默导致 PCAF 和 p300 特异性活性降低。值得注意的是，在 mdx 小鼠中减少的一氧化氮 (NO) 水平对于 KAT 依赖的 Nup153 调节很重要。事实上，用 NO 供体或 KAT 抑制剂 anacardic acid 处理 mdx 心脏组织可使 Nup153 蛋白表达正常化。Nup153 被募集到染色质上，并调节参与心脏重塑的基因的转录，包括肌动蛋白结合蛋白 nexilin。因此，在 mdx 器官培养物中沉默 Nup153 会阻断 nexilin 蛋白的表达。电生理和分子实验表明，Nup153 在正常心肌细胞中的过表达会增加 Ca v 1.2 钙通道的表达和功能。在源自患者特异性诱导多能干细胞的肌营养不良症心肌细胞中也发现了 Nup153 蛋白表达和细胞内定位的改变。重要的是，在杜氏肌营养不良症患者的心脏中也发现了 Nup153 的上调和乙酰化增加。
我们的数据表明，Nup153 是一种表观遗传调节剂，在改变的 NO 信号作用下，介导与早期肌营养不良性心脏重塑相关的基因的激活。
