The Function And Mechanism Of Heterochromatin In The Oxidative Stress-related Retinal Pigment Epithelium Cells

Oxidative stress(OS)-induced retinal pigment epithelium(RPE)cell apoptosis is critically implicated in the pathogenesis of age-related macular degeneration(AMD),one of the leading causes for blindness in the elderly.RPE cells are particularly sensitive to OS because of intense illumination from focal light,high oxygen tension in the macular area,and the phagocytosis of photoreceptor outer segments.Recently,growing evidences suggest that chromatin conformation plays fundamental roles in regulating stress responses.In eukaryotic cells,chromatin is divided into euchromatin and heterochromatin based on differential compaction at the interphase.Although OS-induced gene changes are well studied,little is known regarding the chromatin conformation alterations and the mechanism of action in RPE cells.In my thesis,we used an in vitro human RPE cell and in vivo mouse model to study the chromatin conformation alterations upon OS exposure.We found OS enhanced heterochromatin formation both in vitro and in vivo.Through pharmacological approaches,we further demonstrated that heterochromatin is essential to protect RPE cells from OS-induced cell apoptosis.Finally,we identified suppression of p53 apoptotic pathway is the major mechanism for heterochromatin mediated cell protection.Together,our findings reveal a new protective function of heterochromatin in OS and a mechanistic link between chromatin formation and apoptosis.We propose that targeting the heterochromatin may provide interventional insights in the generation of novel therapeutics for AMD.