The gene encodes tropoelastin which is used to generate elastic fibers that insure proper tissue elasticity. Decreased amounts of elastic fibers and/or accumulation of bioactive products of their cleavage, named elastokines, are thought to contribute to aging. Cellular senescence, characterized by a stable proliferation arrest and by the senescence-associated secretory phenotype (SASP), increases with aging, fostering the onset and progression of age-related diseases and overall aging, and has so far never been linked with elastin. Here, we identified that decrease in either by siRNA in normal human fibroblasts or by knockout in mouse embryonic fibroblasts results in premature senescence. Surprisingly this effect is independent of elastic fiber degradation or elastokines production, but it relies on the rapid increase in HMOX1 after downregulation. Moreover, the induction of HMOX1 depends on p53 and NRF2 transcription factors, and leads to an increase in iron, further mediating downregulation-induced senescence. Screening of iron-dependent DNA and histones demethylases revealed a role for histone PHF8 demethylase in mediating downregulation-induced senescence. Collectively, these results unveil a role for in protecting cells from cellular senescence through a non-canonical mechanism involving a ROS/HMOX1/iron accumulation/PHF8 histone demethylase pathway reprogramming gene expression towards a senescence program.

中文翻译：

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ELN 的非典型作用是通过限制铁依赖性基因表达调节来防止细胞衰老


该基因编码原弹性蛋白，用于生成确保组织适当弹性的弹性纤维。弹性纤维数量的减少和/或弹性纤维分裂时生物活性产物（称为弹性蛋白）的积累被认为会导致衰老。细胞衰老的特征是稳定的增殖停滞和衰老相关的分泌表型（SASP），随着衰老而增加，促进与年龄相关的疾病和整体衰老的发生和进展，但迄今为止从未与弹性蛋白联系起来。在这里，我们发现正常人成纤维细胞中的 siRNA 或小鼠胚胎成纤维细胞中的敲除都会导致过早衰老。令人惊讶的是，这种效应与弹性纤维降解或弹性因子产生无关，但它依赖于下调后 HMOX1 的快速增加。此外，HMOX1的诱导依赖于p53和NRF2转录因子，并导致铁的增加，进一步介导下调诱导的衰老。铁依赖性 DNA 和组蛋白去甲基化酶的筛选揭示了组蛋白 PHF8 去甲基化酶在介导下调诱导的衰老中的作用。总的来说，这些结果揭示了通过涉及 ROS/HMOX1/铁积累/PHF8 组蛋白去甲基化酶途径将基因表达重编程为衰老程序的非典型机制来保护细胞免受细胞衰老的作用。