Age‐Dependent Histone Deacetylase 3 Regulation by <scp>βA3</scp>/<scp>A1</scp>‐Crystallin and Inositol Hexaphosphate in Retinal Pigmented Epithelial Cells Reveals a Novel Pathway in Age‐Related Macular Degeneration

Age-related macular degeneration (AMD), a leading cause of vision loss affecting retinal pigment epithelial (RPE) cells, remains largely unexplained by current genome-wide association studies (GWAS) risk variants. Our research on Cryba1, encoding βA3/A1-crystallin protein, reveals its crucial role in RPE cell function via a novel epigenetic mechanism, also evident in human atrophic AMD samples. Loss of Cryba1 in mouse RPE cells triggers epigenetic changes by reducing histone deacetylase 3 (HDAC3) activity through two mechanisms. First, Cryba1 depletion reduces inositol polyphosphate multikinase (IPMK) expression, which potentially reduces inositol hexakisphosphate (InsP6) generation since IPMK's kinase activity is essential for producing InsP4 and InsP5 as precursors to InsP6. Since InsP4, InsP5, or InsP6 is crucial for HDAC3's interaction with the corepressor's DAD domains, reduced IPMK expression in Cryba1-depleted cells likely diminishes the HDAC3-DAD interaction, leading to a reduction in HDAC3's activity. Second, reduced βA3/A1 protein in Cryba1-deficient cells impairs HDAC3's interaction with casein kinase 2 (CK2), resulting in decreased HDAC3 phosphorylation. Collectively, this increases H3K27 acetylation at the RET promoter region, likely enhancing the transcription of RET, a receptor tyrosine kinase critical for cell survival. Although RET is transcriptionally increased, Cryba1 loss disrupts its protein maturation, causing immature RET protein accumulation. This triggers age-dependent endoplasmic reticulum (ER) stress, potentially contributing to the pathogenesis of AMD. Interestingly, although Cryba1 is not identified as an AMD-linked variant in current GWAS, its loss may be linked to AMD mechanisms. These findings underscore the potential of gene-agnostic and epigenetic therapeutic strategies for treating AMD.