Increased H3K27 trimethylation contributes to cone survival in a mouse model of cone dystrophy

Abstract

Inherited retinal diseases (IRDs) are a heterogeneous group of blinding disorders, which result in dysfunction or death of the light-sensing cone and rod photoreceptors. Despite individual IRDs (Inherited retinal disease) being rare, collectively, they affect up to 1:2000 people worldwide, causing a significant socioeconomic burden, especially when cone-mediated central vision is affected. This study uses the Pde6ccpfl1 mouse model of achromatopsia, a cone-specific vision loss IRD (Inherited retinal disease), to investigate the potential gene-independent therapeutic benefits of a histone demethylase inhibitor GSK-J4 on cone cell survival. We investigated the effects of GSK-J4 treatment on cone cell survival in vivo and ex vivo and changes in cone-specific gene expression via single-cell RNA sequencing. A single intravitreal GSK-J4 injection led to transcriptional changes in pathways involved in mitochondrial dysfunction, endoplasmic reticulum stress, among other key epigenetic pathways, highlighting the complex interplay between methylation and acetylation in healthy and diseased cones. Furthermore, continuous administration of GSK-J4 in retinal explants increased cone survival. Our results suggest that IRD (Inherited retinal disease)-affected cones respond positively to epigenetic modulation of histones, indicating the potential of this approach in developing a broad class of novel therapies to slow cone degeneration.

The role of epigenetic changes in the pathology and treatment of inherited retinal diseases

“…The authors suggested that the neuroprotective activity of LSD1 inhibitors firstly targeted histone modifications, increasing accessibility of chromatin and upregulation of neuroprotective genes, then potentially inhibited transcription of inflammatory genes (Popova et al, 2021). Finally, in a recent study, we found that the ubiquitous H3K27me3 expression seen in wildtype cones was lost in the Pde6c cpfl1 mouse model of achromatopsia (Miller et al, 2022). Administration of GSK-J4, a histone demethylase inhibitor that targets H3K27me3, resulted in increased immunostaining of H3K27me3 in Pde6c cpfl1 cones, and increased cone survival in retinal explants.…”

“…Administration of GSK-J4, a histone demethylase inhibitor that targets H3K27me3, resulted in increased immunostaining of H3K27me3 in Pde6c cpfl1 cones, and increased cone survival in retinal explants. When GSK-J4 was administered to mice via a single intravitreal injection, there were significant transcriptional changes to pathways involved in mitochondrial dysfunction, endoplasmic reticulum stress and key epigenetic pathways (Miller et al, 2022). The role of histone methylation modifications and their contribution to IRD pathology has only recently been investigated, with current studies showing crucial differences in H3K27me3 status in cone and rod photoreceptors, where ubiquitous expression in rods is deleterious to survival, while it is beneficial in cones.…”

“…(A) In the Pde6c cpfl1 mouse model of achromatopsia, decreased expression of the usually ubiquitous H3K27me3 was noted in cone photoreceptors specifically. A significant cone photoreceptor survival was observed when H3K27me3 demethylation was inhibited via GSK-J4 administration in Pde6c cpfl1 retinal explants (Miller et al, 2022). (B) Interestingly, the rd1 mouse model, which shows degeneration of both rod and cone photoreceptors, showed an increase in H3K27me3 expression that coincides with photoreceptor cell death.…”

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

“…In a cpfl1 mouse model with a cone-specific Pde6c gene mutation, retinal cone loss was observed at P14, followed by peak cell death at P24, which was associated with reduced levels of H3K27me3 in retinal cones (Trifunović et al, 2010). Treatment of this model with the H3K27 histone demethylase (HDM) inhibitor GSK-J4, which targets KDM6A, KDM6B, and KDM5 subfamilies (with KDM5 responsible for demethylation of H3K4me1/2/3 (Heinemann et al, 2014)), resulted in a significant increase in optic cone photoreceptor numbers, suggesting a potential role for H3K27me3 deletion in cone degeneration (Miller et al, 2022). By contrast, in the rd1 mouse model of RP, deletion mutations in the rod-specific Pde6β gene led to increased H3K27me3 levels in postnatal retinas, while treatment with the HMT inhibitor DZNep delayed rod death by downregulating NRL and its downstream target NR2E3 to protect rods (Zheng et al, 2018).…”

“…Recent research has demonstrated that modulation of histone methylation/demethylation can have a protective effect against photoreceptor cell death and degeneration in pathological conditions (Zheng et al, 2018;Popova et al, 2021;Miller et al, 2022). In a cpfl1 mouse model with a cone-specific Pde6c gene mutation, retinal cone loss was observed at P14, followed by peak cell death at P24, which was associated with reduced levels of H3K27me3 in retinal cones (Trifunović et al, 2010).…”