The epigenetic basis for the impaired ability of adult murine retinal pigment epithelium cells to regenerate retinal tissue

Galina Dvoriantchikova,Rajeev J Seemungal,Dmitry Ivanov

doi:10.1038/s41598-019-40262-w

Galina Dvoriantchikova, Rajeev J Seemungal + Show 1 more

Open Access

https://doi.org/10.1038/s41598-019-40262-w

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Journal: Scientific Reports	Publication Date: Mar 7, 2019
Citations: 22	License type: open-access

Affiliation: University of Miami

Abstract

The epigenetic plasticity of amphibian retinal pigment epithelium (RPE) allows them to regenerate the entire retina, a trait known to be absent in mammals. In this study, we investigated the epigenetic plasticity of adult murine RPE to identify possible mechanisms that prevent mammalian RPE from regenerating retinal tissue. RPE were analyzed using microarray, ChIP-seq, and whole-genome bisulfite sequencing approaches. We found that the majority of key genes required for progenitor phenotypes were in a permissive chromatin state and unmethylated in RPE. We observed that the majority of non-photoreceptor genes had promoters in a repressive chromatin state, but these promoters were in unmethylated or low-methylated regions. Meanwhile, the majority of promoters for photoreceptor genes were found in a permissive chromatin state, but were highly-methylated. Methylome states of photoreceptor-related genes in adult RPE and embryonic retina (which mostly contain progenitors) were very similar. However, promoters of these genes were demethylated and activated during retinal development. Our data suggest that, epigenetically, adult murine RPE cells are a progenitor-like cell type. Most likely two mechanisms prevent adult RPE from reprogramming and differentiating into retinal neurons: 1) repressive chromatin in the promoter regions of non-photoreceptor retinal neuron genes; 2) highly-methylated promoters of photoreceptor-related genes.

Highlights

Since nearly 80 percent of sensory information is collected by means of sight, vision loss resulting from traumatic injuries or diseases has significant economic and moral impacts on all levels of society[1,2,3]
Our findings indicate that the majority of RPE promoters are in open or active chromatin, which is characteristic of epigenetically mobile stem cells and progenitors[29,30,31]
This conclusion is supportted by our epigenetic data in which we found a high similarity of RPE chromatin and methylome states with optice vesicle progenitors and retinal progenitor cell (RPC)

Summary

Introduction

Since nearly 80 percent of sensory information is collected by means of sight, vision loss resulting from traumatic injuries or diseases has significant economic and moral impacts on all levels of society[1,2,3]. An ideal reparative strategy for the retina would be for it to heal itself – an ability employed by many species, but is known to be absent in mammals Adult teleost fish, such as zebrafish, and amphibians (X. laevis, Cynops pyrrhogaster) have an outstanding ability to regenerate damaged retina and restore lost sight[9,10,11,12,13,14]. Adult Müller glia and RPE undergo a reprogramming process allowing them to generate progenitors for retinal regeneration after injury in teleost fish and amphibians, the reason why this ability is absent in mammals is not yet understood[9,10,11,12,13,14].

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