Chromatin StructureDevelopmental Biology & Stem CellsDNA Methylation and HydroxymethylationHistone Modifications

Frog Eyes Might Be the Key to Retinal Regeneration

Frog Eyes Might Be Key to Retinal RegenerationOften said to be the windows to the soul, our eyes are one of the main ways we perceive the world around us. Vision loss, whether due to aging or injury, can be devastating and often hinders the ability to work, leading to economic stress [1]. Current treatments for vision loss either involve slowing the rate of vision degeneration or performing invasive surgery to transplant cells into the eye [2]. The authors of a new study, Dvoriantchikova and colleagues, however, suggest exploring a new therapeutic avenue that would hopefully lead to a full restoration of vision by non-invasive surgery based on the surprising biology of amphibians and fish.

After an eye injury, adult amphibians and fish can reprogram their retinal pigment epithelial (RPE) cells and Muller glia cells to produce retinal progenitor cells – cells that have the capacity to develop into new retinal cells [3]. Mammalian RPE cells and Muller glia, however, do not have this regenerative ability [4]. Recent research has shown that epigenetic changes are involved in reprogramming these cells in fish and frogs after injury [4]. Dvoriantchikova and colleagues, therefore, assessed the epigenetic landscape in adult RPE cells from mice, which are mammals, to assess where adult mammalian RPE cells differ from amphibian ones, thus potentially identifying mechanisms and molecular pathways that could be therapeutically targeted in mammals to allow for retinal regeneration.

To begin, the authors isolated RPE cells from adult mice and performed ChIP-seq of four different histone modification marks: H3K4me3 and H3K4me1 – marks for active and open chromatin – and H3K27me3 and H3K9me3 – marks for inactive and closed chromatin. In addition to assessing these marks singly, the authors also looked at them in combination, which allowed for the identification of at least 10 different chromatin states. For example, the combination of the repressive mark H3K27me3 and the active mark H3K4me3 would indicate a region of the genome that may be silent but is poised to be activated. From their ChIP-seq data, the authors found that the majority of the promoter sequences were marked by H3K4me1 and H3K4me3 histone modifications, which mark active and open chromatin and is an epigenetic characteristic of stem cells [5]. Because stem cells are able to differentiate into a variety of different types of cells, this finding suggests that adult RPE cells from mice might be epigenetically primed and able to develop into other types of retinal cells.

As eyes develop, optic vesicle progenitor cells (OVPs) can differentiate into either RPE cells or retinal progenitor cells (RPCs), which then differentiate into six neuronal cell types and one glial cell type in the eye [6]. The authors asked how accessible the chromatin was around known genes involved in the development of OVPs, RPCs, and glial cells in mammalian RPE cells. They found that the majority of OVP, RPC, and Muller glia developmental genes were marked by active histone modifications, and they were all located in regions of low or no DNA methylation, indicating that the epigenetic landscape of adult mammalian RPE cells is very similar to that of progenitor cells.

Ultimately, the injured eye will need progenitor cells to differentiate into photoreceptors to replace the damaged ones, so the authors next asked how epigenetically accessible genes involved in retinal neuron or photoreceptor development were in RPE cells. They found that genes required for retinal neuron development were mostly located in inactive chromatin regions. Genes involved in rod and cone photoreceptor development and phototransduction, however, were located in regions of active chromatin, indicating that genes for photoreceptor development may be accessible and thus expressed in adult RPE cells. This result suggests that adult mammalian RPE cells have the capacity to express genes necessary for them to develop into photoreceptor cells.

But when the authors compared the DNA methylation levels and the histone modifications of the promoter regions of these photoreceptor and retinal neuron developmental genes, they were caught by surprise. Typically, one would expect to see low DNA methylation levels correlate with active histone modifications, indicating that the region is accessible and open to gene expression. Instead, the authors found that the promoters of genes involved in photoreceptor development were marked by active histone modifications but were located in regions of high DNA methylation, a repressive mark. Similarly, the promoters of retinal neuron developmental genes were marked by repressive histone modifications but were located in unmethylated or lowly methylated regions, a characteristic of active chromatin. This inverse relationship between DNA methylation and histone modifications may be a reason why mammalian adult RPE calls cannot regenerate after injury. While the active histone modifications are present, to express these genes, the repressive DNA methylation marks must be removed. The authors suggest that amphibians may have pioneering transcription factors that could induce gene expression of regions with repressive histone marks but otherwise low DNA methylation, or they could also activate DNA de-methylation pathways to remove repressive DNA methylation from regions with active histone modifications. More work needs to be done to investigate these possibilities in amphibian RPE cells.

Overall, this study shows that RPE cells have epigenetic plasticity that is similar to stem cells and optical progenitor cells, but the presence of inversed epigenetic regulation of histone modifications and DNA methylation may be an explanation for why mammalian RPEs cannot regenerate, while amphibian RPEs can. Additional research in both mammalian and amphibian adult RPEs will be important for better understanding this regeneration process. The inverse relationship between DNA methylation levels and histone marks indicate that mammalian RPEs may only be temporarily repressed from expressing photoreceptor or retinal neuron development genes, perhaps needing just a small push to express these genes. As a whole, this study provides the basis for a deeper understanding of eye development and response to injury, which will hopefully lead to more effective and non-invasive treatments for vision loss, all thanks to the marvelous eyes of frogs and fish.




Original article: Dvoriantchikova G, Seemungal RJ, Ivanov D (2019). The epigenetic basis for the impaired ability of adult murine retinal pigment epithelium cells to regenerate retinal tissue. Sci Rep, 9(1):3860. doi: 10.1038/s41598-019-40262-w.

[1] Wittenborn JS, Zhang X, Feagan CW, Crouse WL, Shrestha S, Kemper AR, Hoerger TJ, Saaddine JB; Vision Cost-Effectiveness Study Group (2013). The economic burden of vision loss and eye disorders among the United States population younger than 40 years. Ophthalmology, 120(9):1728-35. doi: 10.1016/j.ophtha.2013.01.068.

[2] Dhamodaran K, Subramani M, Ponnalagu M, Shetty R, Das D (2014). Ocular stem cells: a status update! Stem Cell Res Ther, 5(2):56.

[3] Islam MR, Nakamura K, Casco-Robles MM, Kunahong A, Inami W, Toyama F, Maruo F, Chiba C (2014). The newt reprograms mature RPE cells into a unique multipotent state for retinal regeneration. Sci Rep, 4:6043. doi: 10.1038/srep06043.

[4] Goldman D (2014). Müller glial cell reprogramming and retina regeneration. Nat Rev Neurosci, 15(7):431-42. doi: 10.1038/nrn3723.

[5] Keenen B, de la Serna IL (2009). Chromatin remodeling in embryonic stem cells: regulating the balance between pluripotency and differentiation. J Cell Physiol, 219(1):1-7. doi: 10.1002/jcp.21654.

[6] Fuhrmann S, Zou C, Levine EM (2014). Retinal pigment epithelium development, plasticity, and tissue homeostasis. Exp Eye Res, 123:141-50. doi: 10.1016/j.exer.2013.09.003.

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Stephanie DeMarco

Stephanie DeMarco

Stephanie is a PhD candidate in Molecular Biology at the University of California, Los Angeles where she studies how the parasite Trypanosoma brucei regulates its social behavior. When she’s not wrangling her parasites in the lab, Stephanie likes to write about science, tap dance, and attempt to make the perfect plate of pasta carbonara.