Epigenetic Regulation of the Cell Type-Specific Gene 14-3-3σ

Epigenetic control participates in processes crucial in mammalian development, such as X-chromosome inactivation, gene imprinting, cell type-specific gene expression. We provide evidence that the p53-inducible gene 14-3-3σ is a new example of a gene important to human cancer, where epigenetic mechanisms participate in the control of normal cell type-specific expression, as well as aberrant gene silencing in cancer cells. Like a previously identified cell type-specific gene maspin, 14-3-3σ is a p53-inducible gene; however, it participates in G2/M arrest in response to DNA-damaging agents. 14-3-3σ expression is restricted to certain epithelial cell types, including breast, prostate, whereas expression is absent in nonepithelial tissues such as fibroblasts, lymphocytes. In this report, we show that in normal cells expressing 14-3-3σ, the 14-3-3σ CpG isl, is unmethylated; associated with acetylated histones, unmethylated histone H3 lysine 9;, an accessible chromatin structure. By contrast, normal cells that do not express 14-3-3σ have a methylated 14-3-3σ CpG isl, with hypoacetylated histones, methylated histone H3 lysine 9, an inaccessible chromatin structure. These findings extend the spectrum of cell typespecific genes controlled partly by normal epigenetic mechanisms, suggest that this subset of genes may represent important targets of epigenetic dysregulation in human cancer.