当细胞进入不可逆的周期阻滞状态时,称之为细胞衰老。细胞衰老与机体衰老、衰老相关疾病和肿瘤的发生密切相关。衰老细胞失去原有功能。这一过程伴随着染色质的重组,特别是包含占人类基因组17%的长散在核元件1(LINE1)的异染色质区域变得更松散和更易接近,使得LINE1解除抑制
虽然已发现许多转录因子在不同生物学背景下调控LINE1转录,但在衰老细胞中,FOXA1是唯一已知的结合LINE1并增强LINE1转录的因子
近日,viphjc888黄金城毛志勇教授团队在EMBO reports发表题为The transcription factor PAX5 activates human LINE1 retrotransposons to induce cellular senescence的研究成果,该研究发现调控人LINE1逆转录转座子的新转录因子PAX5。PAX5在5'-UTR的富集激活LINE1并促进细胞衰老和SASP的分泌。该团队亦发现,长寿基因SIRT6结合于PAX5启动子并抑制PAX5表达以抑制LINE1转录,从而抑制细胞衰老。
在该项工作中,研究团队通过分析不同类型衰老细胞中共同上调的LINE1元件的5'非翻译区中的保守结合基序,预测了几种与人类LINE1元件结合以调节其转录的转录因子,并结合LINE1 5'-UTR与荧光素酶融合报告载体筛选并鉴定出PAX5为LINE1启动子活性的新正调控因子。在衰老细胞中,观察到PAX5表达增加,并且PAX5在LINE1元件5'-UTR区域的结合增强,从而促进LINE1转录,加强细胞衰老并促进SASP分泌。研究团队还证明了长寿基因SIRT6通过直接结合PAX5启动子抑制PAX5的转录,而PAX5的过表达消除了SIRT6对压力依赖性细胞衰老的抑制作用。
图 筛选LINE1调控转录因子及PAX5调控LINE1促进细胞衰老模式图
综上所述,该研究团队建立了一种基于细胞衰老中共同上调的LINE1转录本,识别并筛选富集转录因子的方法。阐述了PAX5调控LINE1并促进细胞衰老的分子机制,以及长寿基因SIRT6对PAX5调控的分子机制。该研究发现调控LINE1转录活性的新转录因子PAX5,拓宽了细胞衰老进程中LINE1的调控机制,为抑制LINE1激活和治疗衰老相关疾病的药物开发,提供了全新的靶点。
viphjc888黄金城附属妇产科医院/viphjc888黄金城博士后唐欢胤和博士研究生杨佳庆为本论文的共同第一作者。viphjc888黄金城附属妇产科医院/viphjc888黄金城毛志勇教授为本文的通讯作者。毛志勇教授课题组的许君豪博士研究生、耿安珂助理教授、张伟娜助理教授和蒋颖副教授也参与了该项工作。
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