儿童早老症患者基因组不稳定性增加却并不导致肿瘤发生，提示可能存在抵抗肿瘤转化的机制。我们发现一个LMNA基因突变导致的汉族儿童早老症家系，患者 EGR1表达显著升高。最近研究认为Arf-Egr-C/EBPβ调控轴决定细胞的衰老或者肿瘤转化。据此提出假说：LMNA基因突变可能导致表观遗传修饰改变而促进EGR1表达，而高表达EGR1可能通过促使细胞衰老而对肿瘤转化具有抵抗作用。为验证该假说设计研究：首先利用表观遗传学实验技术检测LMNA突变是否导致EGR1基因所在的染色质区域定位改变及其组蛋白修饰改变；然后体外培养获得早老症模型成纤维细胞并将其进行肿瘤转化，检测转化后细胞的致瘤性和EGR1表达；最后通过CRISPR/cas9技术敲除早老症患者成纤维细胞内EGR1基因，再将敲除细胞系进行肿瘤转化，比较其克隆形成能力和致瘤性改变情况。本研究将阐明EGR1表达上升的机制及其抵抗肿瘤转化的功能。

Genomic instability and subsequent accumulation of DNA damage are important risk factors for tumor inducing. However, the lack of tumors in progeroid patients may suggests some possible mechanisms of tumor transformation resistance. We studied a Han family with progeria caused by a LMNA gene mutation, and found that the EGR1 expression was up-regulated in progeroid patients. Recent study showed that the Arf-Egr-C/EBPβ axis was an important determinant of cellular responses to senescence or tumor transformation. Based on this, we proposed the hypothesis that the LMNA gene mutation can cause the epigenetic change which increase the EGR1 gene expression, and the elevated EGR1 expression level may play an important role in the tumor transformation resistance in patients with progeria. To prove this, firstly, we design experiments to investigate the epigenetics changes of EGR1 gene related to the LMNA mutation; and then, cultured fibroblast cells from the progeria patients or model mice will be transformed to immortalized tumor cells (TRS-progeria), and the transformed cells will be tested the tumorigenicity and EGR1 expression level. Finally, after knocking out (KO) of the EGR1 gene by CRISPR/Cas 9 in the progeria fibroblast cells, the EGR1 KO cells will be transformed into immortalized tumor cells (TRS-progeria-EGR1 KO) , and the clone forming ability and tumorigenicity of TRS-progeria-EGR1 KO cells will be tested and compared with TRS-progeria cells. This study will elucidate the molecular mechanism of EGR1 up-regulation and its function in the tumor transformation resistance, and will benefit to understand the tumor-protective mechanism of progeria.