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Review Articles

Epigenetics and Degenerative Retinal Diseases: Prospects for New Therapeutic Approaches

Barnstable, Colin J. DPhil

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Asia-Pacific Journal of Ophthalmology: July/August 2022 - Volume 11 - Issue 4 - p 328-334
doi: 10.1097/APO.0000000000000520
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Abstract

The levels of protein expression in retinal cells are controlled by the network of transcription factors acting at gene promoters and enhancers and by a series of epigenetic modifications that control whether the transcription factors efficiently access their deoxyribonucleic acid (DNA) binding sites. The activity of both transcription factors and epigenetic modifiers can be altered by enzymes sensitive to intracellular and external conditions and the homeostasis engendered by these mechanisms is disrupted in a variety of eye diseases.

A major goal for therapeutic interventions for degenerative eye diseases is to stop the degeneration in ways that can preserve vision. For monogenic eye diseases that are inherited in a Mendelian fashion, replacing a deficient gene (for recessive traits) or disabling a mutant gene (for dominant traits) is a powerful and attractive approach. This is most applicable to many forms of retinitis pigmentosa (RP), and work in this area has been greatly helped by the availability of mouse mutants that closely mimic the human disease. Even for these simple cases, however, there is growing evidence that the initial defect induces a cascade of secondary effects that lead to cell death and may not be halted by gene therapy alone.1 The situation is more complex for multigenic disease, such as age-related macular degeneration (ARMD), glaucoma, or diabetic retinopathy (DR). All the genetic studies of these diseases to date point to the importance of the confluence of multiple minor changes in gene expression or function. Even the most prominent gene so far associated with ARMD, complement factor H, is a risk factor, not a sole cause of the disease.2 Many different combinations of minor genetic variants can result in the same pathology. These multigenic diseases can be considered as a disruption in cellular homeostasis, and restoration of this homeostasis, or large-scale resetting of patterns of gene expression, can be achieved by epigenetic modification.

In this review, I provide a brief overview of epigenetic modifications, their regulatory role in the retina, and examples of epigenetic disruption in retinal disease. Studies on epigenetic regulation in the retina are providing a large amount of data about the normal development and function of this tissue. More importantly, they point the way to a rich source of possibilities for therapeutic intervention to combat currently untreatable degenerative disease.

Epigenetic Modifications

The 2 most studied epigenetic modifications are methylation of DNA and posttranslational modifications of histone proteins (see Ref.35 for reviews). DNA methylation is an important mechanism for switching off expression of genes but there is growing evidence that this methylation can be dynamic and responsive to environmental conditions, but it seems to be less important for subtle homeostatic regulation. Histone modifications, on the other hand, show the type of dynamic changes required for a regulatory mechanism. There is growing evidence for the role of a third group of epigenetic regulators, the noncoding ribonucleic acids (RNAs). These will be mentioned only briefly as we are still learning about their specificity and role in both the normal retina and in retinal disease.

DNA Methylation

DNA can be modified in a number of ways but the addition of a methyl group to the C5 position of cytosine in the cytosine-guanine (CpG) dinucleotide is the most intensively studied and thought to be the most important (Fig. 1). A group of 5 meth-yltransferase enzymes control this methylation at various points in development and cell replication.6,7 DNA methylation is relatively stable and generally inhibits transcription by either directly interfering with transcription factor-binding or by recruiting methyl-CpG-binding proteins that can have multiple effects on chromatin. Though normally stable, the discovery of a series of DNA demethylases has revisited the reversibility of DNA methylation and a potential active role in both health and disease.5

F1
FIGURE 1:
A, Methy|lation of cytosine. The transfer of a methy| group from S-adenosy| methionine to the 5” position of cytosine is catalyzed by one of a family of 5 methy|transferase enzymes. B, Methylation of cytosine occurs on bases preceding guanosine as indicated in this stretch of sequence.

Histone Modification

In the nucleus, DNA is wrapped around histone complexes to form nucleosomes (Fig. 2). With the correct spacing between these nucleosomes, the complexes can condense to form inaccessible chromatin, heterochromatin, and effectively remove these DNA segments from the regulatory machinery that allows transcription.

F2
FIGURE 2:
Structure of a nucleosome. A strand of 146 base pairs is wound around a histone octamer core of 8 histone molecules, 2 each of H2A, H2B, H3, and H4. Linker sequences of DNA connect adjacent nucleosomes and are the sites of binding of the linker histone, H1. The increased density of nucleosome packing, also controlled by histone modifications, creates heterochromatin which is essentially silent transcriptionally. DNA indicates deoxyribonucleic acid.

The spacing of nucleosomes is, in part, regulated by linker molecules, including isoforms of histone H1. We have previously mapped the expression of H1 isoforms during retinal development and showed that the chromatin condensation accompanying rod photoreceptor development is accompanied by a large increase in the expression of histone H1c.8 The mechanism by which histone H1 can regulate gene expression involves controlled phosphorylation. When cyclin-dependent kinase 2 kinase phosphorylates histone H1, this leads to a more open and accessible chromatin structure.9 Similarly, eviction of histone H1 from promoter regions is an important mechanism for allowing transcription initiation. Although altered histone H1 activity may lead to altered photoreceptor chromatin in a number of retinal disease states, the redundancy created by the multiple isoforms of histone H1 makes it difficult to devise effective therapies that preserve the normal state.

Each nucleosome contains approximately 146 base pairs of DNA wound around a core of 8 histone molecules, 2 each of histones 2A, 2B, 3, and 4 (Fig. 2) (reviewed in Ref.11). A wide variety of posttranslational modifications occur on the exposed N-terminal tails of these histones. The most intensively studied of these are acetylation and methylation. Histone acetylation is generally associated with increased transcription. Histone methylation on the other hand can be associated with either transcriptional activation or transcriptional repression depending on the histone, the amino acid residue, and the extent ofmethylation. For example, dimethylation of lysine at residue 4 on histone H3 (H3K4me2) is generally associated with transcriptional activity as is the trimethyl form, H3K4me3. Conversely, H3K9me2, H3K9me3, and H3K27me3 are all associated with transcriptional repression. Acetylation and methylation, and the removal of these groups, are catalyzed by enzymes that work in complexes that can direct their action to specific sites along the genome. In this way epigenetic modifications can be gene-specific, and many changes can occur without any detectable change in the overall level of histone methylation or acetylation.

One question that has yet to be definitively answered is when epigenetic modifications are controlling cell behavior or whether they are the passive response to other controlling factors. We do know, however, that interfering with these epigenetic modifications can dramatically affect retinal cell development and survival. Some years ago, we showed that inhibiting histone demethylation by the enzyme lysine-specific demethylase 1 (LSD1) prevented the normal development of rodent rod photoreceptors.12 Similarly, blocking histone deacetylation by specifically inhibiting histone deacetylase 1 (HDAC1) also blocked rod development (Fig. 3).13 Whether these inhibitors work by globally changing access to transcriptional machinery, or inhibit the binding of specific transcription factors is not yet known. It is clear, however, that the effects of the inhibitors are specific to certain clusters of genes, suggesting some specificity in the process. Both LSD1 and HDAC1 are components of a macromolecular complex, CoREST, that contains a number of sequence-specific DNA-binding proteins that act as molecular bridges.14,15 If there is heterogeneity in the actions of these histone-modifying enzymes, then it will be possible to modify transcription at selected clusters of genes by using very specific pharmacological agents.

F3
FIGURE 3:
Specific inhibition of HDAC1 blocks rhodopsin expression and rod development. Mouse PN1 retinal explants cultured with vehicle (A) 0.1 µM HDAC1 inhibitor (B) or 0.5 µM HDAC1 inhibitor (C) for 96 h. Tissue sections were then stained with anti-rhodopsin. Quantification of multiple images shows that the inhibitor reduced rhodopsin expression by 70% and 90%, respectively. Scale bar = 20 µm. Figure adapted from Ref.13 HDAC1 indicates histone deacetylase 1; PN1, postnatal day 1.

Noncoding RNA

Epigenetic modification of transcription has most commonly been studied using protein-coding genes. There is, however, increasing evidence for control of gene expression, particularly at the translational level, by noncoding RNAs in retinal disease. Aberrant expression of long noncoding RNAs has been detected in retinas from animal models of DR.16 Differential microRNA expression patterns have been found in endothelial cells subjected to high glucose, and several of these microRNAs were also altered in clinical samples from DR patients.17 Although much of the data is currently correlational, there are beginning to be mechanistic links between individual noncoding RNAs and retinal disease. In experimental choroidal neovascularization, the miR-29s can negatively regulate the metalloproteinase MMP–2, an enzyme involves in angiogenesis.18 MiR–29s is in turn negatively regulated by nuclear factor kappa B (NFkB). These results have been interpreted as showing how NFkB activation can lead to increased angiogenesis. The NFkB pathway itself can be modulated by microRNAs because in animal models of DR miR–874 induces degradation of NFkB and reduces vascular abnormalities back to near control values.19 These and other examples show that noncoding RNAs are likely to play a key role in retinal disease and may be valuable therapeutic targets.

Epigenetic Modifications in Retinal Degenerative Diseases

It is well documented that epigenetic changes accompany aging in the retina.20 Because most of the major retinal degenerative diseases increase with age, there has been interest in determining whether diseases could reflect accelerated aging and the associated changes in the epigenome. Although only a correlation, there is growing evidence for altered DNA methylation in retinal disease. Several studies have identified an important role for the DNA methylase DNMT1 in normal retina development.21,22 It has since been shown in both animal models and human tissue that there are methylation changes in retinal disease. In animal models of RP, dying photoreceptors showed increased levels of cytosine methylation.23 The methylation changes correlated with increased methyltransferase activity and abnormalities in chromatin structure.24 This has led to the suggestion that inhibiting DNA methylation might be of therapeutic benefit in RP.5 Increased DNA methylation has also been found in both human and animal versions of Dr. This increased methylation continued after normalization of glucose levels and is thought to be an important component of the metabolic memory associated with diabetes and diabetic complications.2527 Altered DNA methylation may also be involved in the progression of ARMD (reviewed in Ref.3). For example, in ARMD tissues, hypermethylation of glutathione S-transferase isoform promoters correlates with decreased expression of their respective genes and proteins, possibly increasing the susceptibility to oxidative stress.28 Similarly, methylation profiling of retinal pigment epithelium (RPE) from donor eyes of individuals with ARMD revealed differential methylation of at least 4 genes that have been implicated in ARMD pathways.29 Interestingly, there was no global change in methylation detected. Another study using retinal samples found changes in DNA methylation at the site of the ARMS2 (HTRA1) (age-related maculopathy susceptibility 2-HtrA serine peptidase 1) locus that had previously been shown to be associated with ARMD, and at a novel site, suggesting that this approach may lead to the identification of new disease path-ways.30,31 Several studies have examined DNA methylation in peripheral blood of ARMD patients, but it is not clear how well this reflects events in the retina as most epigenetic changes seem to be tissue, or even cell, specific. The alternative, studying postmortem tissue also has disadvantages, namely the variable loss of cells and the possibility of postmortem changes. A recent bioinformatic study identified 456 differentially expressed genes and 4827 intra-genic differentially methylated CpGs between ARMD and controls.32 Because intragenic sites may represent important structural determinants of chromatin, or be the loci of a variety of noncoding RNAs, these methylation sites may reveal another layer of genome regulation.

Using surgically excised fibrovascular membranes from patients with proliferative DR, 132 genes were found to be hypomethylated and increased in expression, and 172 genes were hypermethylated and decreased in expression.33 Many of these genes belonged to pathways implicated in DR suggesting that they may be involved in DR pathophysiology. Although altered expression of over 300 genes may seem a large number, just as important is the implication that the vast majority of genes were not altered, indicating great selectivity in the changes.

Another disease in which differential methylation of multiple autoinflammatory genes has been detected is retinopathy of prematurity.34 These genes included brain-derived neurotrophic factor, C-reactive protein, angiopoietin 1, and a member of the tumor necrosis factor receptor superfamily. These findings may allow the development of new therapies, but more immediately allow the diagnosis of infants most susceptible to retinopathy of prematurity.

Although the focus of this review is on the retina, methyl-ation changes seem to be a general component of degenerative diseases. In the brain, there is a good correlation between DNA methylation changes and diseases, such as Huntington disease and Parkinson disease.35,36 They are almost important in other ocular compartments. For example, hypomethylation of ion channel genes essential for corneal endothelium function has been detected in Fuchs endothelial corneal dystrophy.37

The role of histone modifications in complex diseases such as ARMD is less clear, in part because of the heterogeneity of the disease and in part because of the many different histones and their modifications. Most of the available data has been obtained from either cell culture or animal studies. In RPE cells, hypoxia leads to an increase in histone demethylases and an increase in expression of genes including a group of proangiogenic genes.38 Sirtuin 1, a widely expressed histone deacetylase, had a lower expression in RPE cells from ARMD patients than from controls.39 Other studies on RPE in early dry ARMD have detected an overall decrease in chromatin accessibility.40 This was found to be due, in part, due to overexpression of the histone deacetylase HDAC11. Though far from complete, the data so far suggest that altered histone modification can have widespread effects in ARMD including changing expression of genes that may aid disease progression.

DR can continue to progress long after the original hyperglycemic insult has been corrected. There is extensive evidence that this phenomenon of “metabolic memory” is regulated in part by DNA methylation.25,27 Specific methylation changes have been identified in genes regulating damage to mitochondrial DNA, certain gene promoters and encoding specific metalloproteinases.26,4143 Upregulation of a histone acetyltransferase and 2 histone arginine methyltransferases have been detected in diabetic RPE.4446 In an animal model of diabetic, decreased histone deacetylase and subsequent increased H3K9 and H3K56 acetylation have been proposed as a mechanisms for decreased expression of brain-derived neurotrophic factor and increased expression of vascular endothelial growth factor.47 In a rat model of DR, it has been shown that D-amino acid oxidase (DAAO) mRNA and protein are reduced by 66% and 70%, respectively. This enzyme is responsible for regulating the levels of D-serine, a molecule that can protect against neurodegeneration, possible through its action at N-methyl-D-aspartate (NMDA) receptors.48 In the diabetic animals it was found that the DNA methylating enzyme DNMT1 was increased and that the proximal promoter region of DAAO was more highly methylated.49 The direct link to DR was confirmed by using DAAO-expressing virus to increase levels in the retina. Restoring DAAO levels normalized the number of retinal ganglion cells, endothelial cells, and pericytes.

There are fewer studies on the role of epigenetic changes in glaucoma. Comparison of lamina cribrosa cells from glaucomatous human eyes with those from normal eyes found globally increased DNA methylation.50 Interestingly, however, DNA methylation around genes such as transforming growth factor beta was decreased and led to increased transcription. In experimental models of retinal ganglion cell death induced by optic nerve crush or ischemia, there is a peak of histone deacetylation after 5 days.51 Inhibition of HDAC3 gave some protection against ganglion cell death in the DBA/2J model of pigmentary glaucoma, suggesting that these enzymes may be damaging rather than part of a protective response.52

The Potential of Epigenetic Therapy in Eye Disease

The array of epigenetic changes described above for several retinal diseases has led to the idea that using pharmacological agents to reverse these changes might decrease or reverse disease symptoms. A number of the drugs available have come from cancer biology studies where they have been used in an attempt to lessen tumor growth either by directly causing cell death or by inducing differentiation into more benign forms. For example, it is known that hypermethylation is an inhibitor of tumor suppressor genes and it has been suggested that inhibiting the methylases responsible for this might provide some therapeutic benefit.53

Some of the most extensive data in the eye comes from studies on mouse models of RP as some of these models carry mutations in the same genes that can cause the human disease. In a study of multiple animal models of RP, the methyltransferase inhibitor decitabine was shown to reduce RP phenotypic progression.23 Inhibition of DNA methylation was found to suppress RPE transdifferentiation in human epiretinal membranes.54 This study used 5-AZA-dC, a drug being tested in cancer therapy, and showed therapeutic effects without any measurable toxicity. Whether it can be effective in the intact eye has yet to be shown.

Studies in mouse photoreceptor degeneration mutants using the general HDAC inhibitors trichostatin A or valproic acid gave significant neuroprotection.55,56 These compounds, and sodium butyrate have been tested in human RP patients. Valproic acid resulted in some improvement in visual acuity and visual fields, but there are also reports of some patients showing worse outcomes with this drug.57 In addition, systemic application of these broad-spectrum inhibitors causes a number of unwanted side effects. It is likely that more specific inhibitors, and the development of selective ocular delivery, will provide better treatments. Emerging data seem to support this.

In studies using the rd10 mouse mutant, that carries a mutation in the phosphodiesterase 6 gene, we showed that inhibitors of either a lysine demethylase, LSD1 or KDM1, or a specific histone deacetylase, HDAC1, were able to arrest the degeneration of rod photoreceptors (Fig. 4).58 This block required the continued presence of the inhibitor as degeneration resumed when the inhibitor was removed. When the effect of these inhibitors on global gene expression was measured, several patterns emerged. The first was an increase in chromatin accessibility and upregulation of neuro-protective genes, including those of the Wntpathway. A second was a dramatic decrease in the expression of inflammatory genes. This effect of LSD1 inhibitors on inflammation was 2–fold. One effect was in the nucleus through an alteration of the epigenetic environment of certain inflammatory genes. The second was an effect in the cytoplasm on the methylation of the transcription factor NFkB. Demethylation of the p65 subunit of NFkB enhances its ability to activate expression of inflammatory genes.59,60 This demethylation is catalyzed by LSD1/KDM1 and the inhibitors of this enzyme effectively decrease the activity of NFkB and reduce expression of its target genes. This finding emphasizes the fact that a number of epigenetic modulators, and therefore their inhibitors, can act in multiple ways. Though pathways by which LSD1/KDM1 inhibitors can rescue rods in RP models have been identified, it is less clear how HDAC inhibitors exert similar effects. HDAC1 inhibitors, such as romidepsin, are effectively inhibited rod degeneration and had effects on both the acetylation of specific retinal genes and also on inflammation.58 Whether this is solely through their actions on HDACs in the nucleus or they have other actions on cytoplasmic enzymes has yet to be determined. Because both LSD1 and HDAC1 are part of the CoREST complex, it is possible that inhibiting either enzyme can affect the activity of the whole complex. In addition to studies on RP models, an inhibitor of LSD1 histone demethylase has also been shown to provide neuroprotection for ganglion cells stressed by glutamate and NMDA neurotoxins, suggesting that this approach may have a broader benefit for retinal diseases.61

F4
FIGURE 4:
Treatment of mouse rd10 retinas with inhibitors specific for LSD1 and HDAC1. Microscopic images of retina sections from P24 rd10 and WT mice treated from P9 until P24 with GSK (LSD1 inhibitor), romidepsin (HDAC1 inhibitor), or saline (control), stained with GFAP (red), and nuclear counterstained with Hoechst33358. Treatment of wild-type retinas shows no detectable toxicity. Rd10 retinas at this stage show dramatic loss of rod photoreceptors and decrease in the ONL. There is also a strong Muller glial response as shown by the increased GFAP staining. Treatment with either the LSD1 inhibitor or the HDAC1 inhibitor shows a strong preservation of rods. Functional tests of vision in animals treated with these inhibitors preserved at least 60% of visual acuity. Scale bar = 20 mm. Figure adapted from Ref.52 HDAC1 indicates histone deacetylase 1; GCL, ganglion cell layer; GFAP, glial fibrillary acidic protein; LSD1, lysine-specific demethylase 1; ONL, outer nuclear layer; WT, wild type.

In addition to histone modulators, studies have investigated alteration of chromatin compaction as a general strategy for rod preservation in RP. Both inhibition of DNA methylation and inhibition of compaction mediated through the PRC2 (polycomb repressive complex 2) complex led to increased rod survival in the rd1 mouse model of RP.23,62,63 The use of a variety of inhibitors that act in different ways will allow us to determine the relative importance of nuclear and cytoplasmic actions.

As we learn more about the epigenetic mechanisms controlling the expression of genes, new therapeutic options are likely to become available to arrest progression of retinal diseases. For example, a multiprotein complex PRC1, polycomb repressive complex 1, monoubiquinates lysine 119 of histone H2A, also promotes chromatin compaction through activating the PRC2 complex. Genetic removal of one of the PRC1 components, BM11, promoted survival of rod photoreceptors in rd1 mouse mutants.63 How many components of these epigenetic modifying complexes are druggable remains to be seen, but new targets are being discovered and hold a lot of potential.

Epigenetics and Regenerative Medicine

Although we are likely to see a range of epigenetic modifiers moving into clinical practice to block or slow degeneration of retinal cells, there is also a need to restore vision to patients who have irreversibly lost retinal cells. Rapid progress has been made in developing methods to generate retinal cells from stem cells, including induced pluripotent stem cells from the patients themselves. At present these methods are slow and most still result in the generation of multiple cell types. There is also current interest in reprogramming Muller glia to provide a source of cells to replace those lost through disease.64,65 As we better understand the epigenetic processes regulating the formation of cell types during normal development, we will be able to direct the differentiation of stem cells more efficiently into the cell types desired, and possibly produce cells more rapidly. Most of the studies published to date have focused on mapping the epigenetic changes during development (reviewed in Ref.66). In a few cases, epigenetic modifier drugs have been used in animal models, but these have blocked development rather than channeling it in a specific pathway or changing the time course.20,61 Nevertheless, as we learn more about the epigenetic controls of development, it is highly likely that selective manipulation of the epigenome will be able to aid the production of cells suitable for transplantation into patients with degenerated retinas.

Summary and Prospects

An understanding of the role of epigenetic changes in retinal disease is still in its infancy. There is very strong evidence that the epigenome is dynamic and plays an important role in retinal development and maintenance. It is highly likely that the primary disease-causing events led to a cascade of secondary effects, some of which are the causes of cell death. Because manipulation of the epigenome can act simultaneously on many genes, altering the activity of appropriate epigenetic modifiers can restore many of these genes to their normal levels.

Although the detailed data are currently only available in animal models, results so far are very promising. These data have also removed one early concern with such manipulations, namely that altering activity of epigenetic modifiers would lead to large-scale cell disruption and death. As new epigenetic modifier drugs become available, we can expect finer specificity in altering retinal gene expression. Topical, or intraocular delivery, is likely to circumvent any systemic effects and allow adoption of these drugs in ophthalmology more easily than for other organs.

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Keywords:

DNA methylation; HDAC1; histone acetylation; histone methylation; LSD1

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