DNA Methylation Dynamics in a Mouse Model of Retinitis Pigmentosa

Lu Huang; Lydia Tai Wai; Kin-Sang Cho; Ajay Ashok; Maximilian Braun; Menglu Yang; Karen Chang; Anton Lennikov; Sarita Pooranawattanakul; Farris Elzaridi; Hio Tong Kam; Yizhen Tang; Qingfeng Li; Dong Feng Chen

doi:10.1016/j.ajpath.2025.05.021

DNA Methylation Dynamics in a Mouse Model of Retinitis Pigmentosa

Am J Pathol. 2025 Jun 24:S0002-9440(25)00207-X. doi: 10.1016/j.ajpath.2025.05.021. Online ahead of print.

Authors

Affiliations

¹ Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts.
² Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts.
³ Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: dr.liqingfeng@shsmu.edu.cn.
⁴ Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts. Electronic address: dongfeng_chen@meei.harvard.edu.

PMID: 40571124
DOI: 10.1016/j.ajpath.2025.05.021

Abstract

Retinitis pigmentosa (RP) is a group of sight-threatening genetic diseases characterized by progressive degeneration of photoreceptors, leading to severe vision loss from childhood to adulthood. With limited treatment options, understanding the molecular mechanisms underlying RP is crucial. Evidence points to increased DNA methylation, especially in degenerating photoreceptors, as a contributing factor to retinal damage in RP. To exploit the molecular insights into methylation-driven pathways, this study investigates the DNA methylation patterns and their potential roles in photoreceptor degeneration in a mouse model of RP, specifically mice carrying a rhodopsin deficiency (Rho^-/-). We observed elevated levels of DNA methyltransferases (DNMTs) and DNA methylation during photoreceptor degeneration. Importantly, weekly intravitreal injections of the pan DNMT inhibitor decitabine in Rho^-/- mice significantly improved photoreceptor morphology and visual function, as evidenced by electroretinogram, spectral-domain optical coherence tomography, and optomotor response-based visual behavior assays. Further histologic and immunohistochemical assessments revealed increased survival of cone photoreceptors and thicker outer nuclear layers in decitabine-treated mice compared with controls. Together, these findings reveal that the dynamics of DNA methylation correlate with photoreceptor degeneration. Inhibition of DNMTs mitigated the morphologic and functional impairments associated with the genetic defects in photoreceptors, suggesting that targeting DNA methylation could be a viable therapeutic strategy for neuroprotection in RP.