Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, PR China.
Mech Ageing Dev. 2011 Apr;132(4):180-6. doi: 10.1016/j.mad.2011.03.004. Epub 2011 Mar 29.
Lsh, a protein related to the SNF2 family of chromatin-remodeling ATPases, is a major epigenetic regulator that is essential for DNA methylation and histone acetylation at repetitive elements. Lsh represses endogenous p16(INK4a) expression by recruiting HDAC to the p16(INK4a) promoter, which in turn delays cell senescence. However, the molecular mechanisms that govern loss of Lsh expression during cellular senescence have yet to be elucidated. Here we investigate the transcriptional regulation of the human Lsh promoter. We find that the minimal Lsh promoter is located between positions -216 and -119 relative to the transcription start site, and contains two putative E2F binding sites. Ectopic E2F1 increases expression of Lsh at both transcriptional and translational levels. E2F1 physically interacts with the Lsh promoter by binding to each of the two putative binding sites and transactivates the Lsh promoter. E2F1 also induces Lsh protein expression and transactivates the Lsh promoter in 2BS cells. At the same time, E2F1-induced Lsh promoter activity is reduced in senescent cells compared to young cells. These results indicate that E2F1 plays a crucial role in transcriptional control of the human Lsh gene and the decrease of Lsh expression in senescent cells is related to the repression of E2F1.
Lsh 是一种与染色质重塑 ATP 酶 SNF2 家族相关的蛋白质，是一种主要的表观遗传调节剂，对于重复元件的 DNA 甲基化和组蛋白乙酰化至关重要。Lsh 通过将 HDAC 募集到 p16(INK4a) 启动子上来抑制内源性 p16(INK4a) 的表达，从而延缓细胞衰老。然而，调控细胞衰老过程中 Lsh 表达丧失的分子机制尚未阐明。在这里，我们研究了人 Lsh 启动子的转录调控。我们发现，相对于转录起始位点，最小的 Lsh 启动子位于-216 到-119 位置之间，包含两个假定的 E2F 结合位点。异位 E2F1 在转录和翻译水平上均增加 Lsh 的表达。E2F1 通过结合两个假定的结合位点与 Lsh 启动子物理相互作用，并转录激活 Lsh 启动子。E2F1 还在 2BS 细胞中诱导 Lsh 蛋白表达并转录激活 Lsh 启动子。与此同时，与年轻细胞相比，衰老细胞中 E2F1 诱导的 Lsh 启动子活性降低。这些结果表明，E2F1 在人 Lsh 基因的转录调控中起着至关重要的作用，衰老细胞中 Lsh 表达的降低与 E2F1 的抑制有关。
