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Peng Shang, Rachel Daley, Emma Rose Mahally, Nadezda A Stepicheva, Sayan Ghosh, Haitao Liu, Anastasiia Strizhakova, Olivia Chowdhury, Victoria Koontz, Stacey L Hose, J. Samuel Zigler, Jiang Qian, Debasish Sinha; HDAC11 is a crucial regulator for visual cycle genes and retinal function. Invest. Ophthalmol. Vis. Sci. 2022;63(7):4115 – F0352.
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It has been reported that RPE cells isolated from age-related macular degeneration (AMD) patients present decreased chromatin accessibility and reduced expression of RPE signature genes, likely due to the upregulation of histone deacetylase 11 (HDAC11), an enzyme that deacetylates the histones and results in a more closed chromatin structure. In this study, we aim to dissect the role of HDAC11 in regulating RPE genes and RPE function.
Best1-Hdac11 constitutive knock-in (KI) mice were generated for this study. Hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining were performed on retina sections from 12-month-old WT and Hdac11 KI mice. Electroretinography (ERG) was performed on Hdac11 KI and age-matched WT mice to measure retina function. RPE flatmount cultures and Hdac11 adenoviral constructs were used for Hdac11 gain of function studies in vitro. Quantitative PCR analyses were performed to evaluate mRNA levels of genes involved in multiple biological processes in RPE cells from WT and Hdac11 KI mice or RPE flatmounts.
Histological results revealed decreased pigmentation of RPE cells, increased thickness of Bruch’s membrane (BM), BM breaks, and abnormal photoreceptor outer segments in 12-month-old Hdac11 KI mice. ERGs showed decreased a, b and c wave amplitudes in 12-month-old Hdac11 KI mice indicating impaired retina function compared to WT mice. Immunofluorescence experiments showed reduced opsin and PNAL (peanut agglutinin lectin) staining in 12-month-old Hdac11 KI mice. Decreased expression of visual cycle genes such as Rpe65 and Lrat were found in Hdac 11 KI mice relative to WT mice at both 5 and 12 months of age. RPE flatmounts overexpressing Hdac11 also showed significantly decreased expression of visual cycle genes (Rpe65, Lrat, Rdh5, Rbp1, Rgr), but not lysosomal genes (Atp6v0, Lamp1), or genes involved in other processes such as Il1b, Bcl-2, and Sox9. No significant changes in the expression of Hdac1, Hdac2, Hdac6, Hdac7, Hdac8 were found in RPE flatmounts overexpressing Hdac11.
Our results suggest that HDAC11 may control the chromatin accessibility for RPE-specific genes, such as visual cycle genes, and thereby normalize physiological functions of the RPE/retina. The current study provides mechanistic insight as to the upregulation of HDAC11 reported in patients with dry AMD and thereby provides a novel therapeutic avenue for delaying the progression of the disease.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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