The Potential Role of Epigenetic Mechanisms in the Development of Retinitis Pigmentosa and Related Photoreceptor Dystrophies

Abstract

Retinitis pigmentosa and related photoreceptor dystrophies (RPRPD) are rare retinal diseases caused by hereditary gene mutations resulting in photoreceptor death, followed by vision loss. While numerous genes involved in these diseases have been identified, many cases have still not been associated with any gene, indicating that new mechanisms may be involved in the pathogenesis of these photoreceptor dystrophies. Many genes associated with RPRPD regulate photoreceptor specification and maturation in the developing retina. Since retinal development begins with a population of equivalent, proliferating retinal progenitor cells (RPCs) having a specific “competence” in generating all types of retinal neurons, including cone and rod photoreceptors, we tested the epigenetic changes in promoters of genes required for photoreceptor development and genes associated with RPRPD during RPC differentiation into cone and rod photoreceptors. We found that promoters of many of these genes are epigenetically repressed in RPCs but have no epigenetic restrictions in photoreceptors. Our findings also suggest that DNA methylation as an epigenetic mark, and DNA demethylation as a process, are more important than other epigenetic marks or mechanisms in the pathogenesis of these diseases. Most notably, irregularities in the DNA demethylation process during the RPC-to-photoreceptor transition may significantly contribute to retinitis pigmentosa (RP) pathogenesis since genes with hypermethylated promoters in RPCs account for at least 40% of autosomal recessive RP cases and at least 30% of autosomal dominant RP cases. Thus, we proposed an epigenetic model according to which unsuccessful demethylation of regulatory sequences (e.g., promoters, enhancers) of genes required for photoreceptor development, maturation, and function during the RPC-to-photoreceptor transition may reduce or even eliminate their activity, leading to RPRPD without any inheritable mutations in these genes.

Decitabine improves MMS-induced retinal photoreceptor cell damage by targeting DNMT3A and DNMT3B

“…DNA methylation and demethylation are important epigenetic mechanisms in the pathogenesis of retinal diseases. Based on this, Dvoriantchikova et al (2022) proposed an epigenetic RP model by suppressing demethylation of genes which are essential for transition from RPC-to-photoreceptor without any mutations. DNA methyltransferase and demethylase have been recognized to be involved in the repair of C/T mismatch caused by deamination of methylated cytosine in BER pathway, and PARP1 could regulate the activity of target protein through recruitment of demethylases ( Maiti and Drohat, 2011 ; Weber et al, 2016 ; Sutcu et al, 2019 ; Jiang et al, 2020 ).…”

Base and Prime Editing in the Retina—From Preclinical Research toward Human Clinical Trials

“…The need to understand mutations in the epigenetic landscape is crucial to moving forward with additional therapies and targets for human patients. While there are not many studies examining the effects of epigenetic mutations in IRDs [ 53 ], many epigenetic marks play a role in the expression and variability of retinal genes involved in phototransduction and development [ 54 , 55 ]. It is important to take into consideration the potential effects that DNA or histone methylation have on the pathogenesis of IRDs over time.…”

The role of epigenetic methylation/demethylation in the regulation of retinal photoreceptors

“…However, emerging evidence also suggests that epigenetic modifications may contribute to the pathogenesis of these disorders. Specifically, unsuccessful demethylation of regulatory sequences (e.g., promoters, enhancers) during the transition from retinal progenitor cells to photoreceptors may reduce or eliminate the activity of genes required for photoreceptor development, maturation, and function, potentially leading to RPRPD even in the absence of genetic mutations (Dvoriantchikova et al, 2022). While further study is needed to confirm the extent of epigenetic contributions to RP and RPRPD, these findings suggest a potential new avenue for therapeutic intervention.…”

“…In contrast, the role of DNA methylation and DNA demethylation pathways in the differentiation of RPCs to non-photoreceptor retinal phenotypes may be less critical (Dvoriantchikova et al, 2019). Another study confirmed these findings, indicating that gene promoters essential for rod and cone photoreceptor fate specification and maturation, such as Crx, Nrl, Nr2e3, Pde6a, Pde6g, Pde6c, Pde6h, Gnat1, Rho, Ush2a, Prph2, etc., are hypermethylated in RPCs and demethylated during the transition from RPCs to photoreceptors (Dvoriantchikova et al, 2022). Additionally, the Wnt signaling pathway can inhibit cellular differentiation in the retina (Kubo et al, 2005).…”