Epigenetic Regulation of Autophagy by the Histone Deacetylases in Retinal Pigment Epithelium

Phagocytosis and autophagy within the retinal pigment epithelium (RPE) is essential for both the maintenance of retinoid levels and degradation of photoreceptor outer segments (POS). Autophagic dysregulation in the RPE leads to an abnormal accumulation of damaged cellular components, lipofuscin, and extracellular drusen deposits, all of which have been associated with the pathogenesis of age related macular degeneration (AMD) and RPE cell death. Histone deacetylases (HDACs) are part of the epigenetic machinery acting as key regulators of chromatin remodeling process and gene transcription. Recent studies have shown the epigenetic regulation of autophagy by HDACs in different cell types. Inhibiting HDACs has emerged as a promising strategy to induce cell death in malignant cells. Findings from our lab have shown the differential expression of several HDACs in human RPE at both the mRNA and protein levels, in advanced dry AMD compared to the normal age-matched control eyes. Our preliminary studies also indicate that selective inhibition of HDACs in human RPE induce upregulation of several autophagy related genes. Therefore, the aim of this proposal is to understand the mechanism of HDAC mediated regulation of autophagy and its critical role in AMD pathogenesis.