Transcriptional activation of the senescence regulator Lsh by E2F1

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.