Journal of Eye Study and Treatment

Mini Review

Epigenetic Modification and Retinal Degeneration: Evidence of New Potential Therapeutic Targets

Yimeng Fan and Danian Chen*

Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China

Received: 10 December, 2018

Accepted: 22 December, 2018

Version of Record Online: 08 January, 2019


Chen D, Fan Y (2019) Epigenetic Modification and Retinal Degeneration: Evidence of New Potential Therapeutic Targets. J Eye Stud Treat 2018(1): 01-08.

Correspondence should be addressed to

Danian Chen, China


DOI: 10.33513/JEST/1801-05

Retinitis Pigmentosa (RP) is a group of hereditary neurodegenerative retinal diseases affecting photoreceptor cells and causing blindness in humans. Epigenetic modification, including DNA methylation, histone post-translational modifications and changes in nucleosome positioning, regulates gene expression, cellular differentiation and development that do not result from alterations in the DNA sequences. In the pathogenesis of RP, epigenetic modifications played an important role, including DNA Methyltransferases (DNMTs), Poly-ADP-Ribose Polymerase (PARP), Histone Deacetylases (HDACs), Bmi1, histone H3 lysine trimethylation at H3K27 (H3K27me3), and PI3K-Akt pathway. At present, we do not have effective therapy for RP, but epigenetic modification may shed light on its therapy. In this review, we provided an overview of the epigenetic modifications involved in RP and evidence of new potential therapeutic targets for RP.


  • Epigenetic modification played an important role in the pathogenesis of RP.
  • Epigenetic modification involved in RP includes DNA Methyltransferases (DNMTs), Poly-ADP-ribose Polymerase (PARP), Histone Deacetylases (HDACs), Bmi1, histone H3 lysine trimethylation at H3K27 (H3K27me3), and PI3K-Akt pathway.
  • Blocking certain epigenetic modifications may protect photoreceptor cells and prolong their survival, which suggests a potential therapeutic strategy for RP.

Open Questions

  • How can therapy targeting on epigenetics modification be translated from preclinical studies into clinical trials?
  • How to specialize the epigenetic target with minimal off-target effects and maximal therapeutic benefits?
  • Would the blockers of certain epigenetic modifications work for patients with gene mutation as well?

Retinitis Pigmentosa (RP) is a set of heredity retinal diseases that feature the degeneration of rod and cone photoreceptors, with a worldwide prevalence of approximately 1:4000 [1]. Though RP is a highly variable disorder, many patients fall into a classic pattern of progression. The degeneration of peripheral rod photoreceptors causes initial night vision loss. As rod degeneration continues, patients experience tunnel vision. Finally, patients will lose daylight vision and progress to complete blindness due to macular cone loss [2]. Although most of RP cases are non-syndromic (lesions are confined to the eye), 20-30% of patients with RP have extraocular symptoms [3]. Such cases fall within more than 30 different syndromes. The most frequent syndromic form is Usher’s syndrome, in which hearing impairment is involved [4]. Hardest-Biedl syndrome is another major form of syndromic RP, in which RP is associated with obesity, cognitive impairment, polydactyl, hypogenitalism, and renal disease [5,6]. Other rare syndromic forms of RP include Bassen-Kornzweig syndrome, Refsum’s disease and α tocopherol transport protein deficiency [7]. RP is a major cause of visual disability and blindness, and the most common Inherited Retinal Dystrophy (IRD) [3]. However, like most of the neurodegenerative diseases, an effective treatment remains an unmet medical need. Present treatments for RP include vitamin supplementation, neuro-protective factor-secreting intraocular implants, and electronic retinal prostheses [8-12]. However, these treatments are only minimally effective in slowing down the progression of the disease or merely rescuing vision.

Mechanism of Pathogenesis

The retinal degeneration1 (rd1 or rd) human homologous mouse is one of the most-studied models for RP. It is characterized by a loss-of-function mutation in the gene encoding for the β-subunit of rod photoreceptor cGMP Phosphodiesterase 6 (PDE6) [13]. About 4-5% of patients are suffering from mutations in the PDE6 gene [14]. Non-functional PDE6 leads to accumulation of cGMP which play a key role in the phototransduction cascade. Excessive cGMP triggers the degeneration of photoreceptors [15,16]. The mechanisms of rd1 retina pathogenesis may shed light on its therapy, including apoptotic and non-apoptotic cell death, cell-intrinsic factors, disrupted intracellular Ca2+ homeostasis, and epigenetic modifications [17-21].

Gene Mutations

Currently, 84 genes and 7 candidate genes have been linked to non-syndromic RP, while 40 genes are related to syndromic RP (RP accompanied by extraocular symptoms) [3,22,23]. These genes encode proteins that play a role in phototransduction cascade, visual cycle, ciliary structure and transport, interphotoreceptor matrix, and so on [3].

Epigenetic Modifications

Although gene mutations play a role in the pathogenesis of RP, epigenetic mechanism is another powerful factor. Epigenetic modification regulates gene expression, cellular differentiation and development that do not result from alterations in the DNA sequences but via the chemical modifications of DNA and histones [24]. Previous studies have reported epigenetic modifications play a role in a variety of retinal diseases, including retinal fibrosis, retinoblastoma, RP, age-related macular degeneration, and diabetic retinopathy [25-29]. Recently, dysregulation of DNA methylation and histone acetylation has been found to be involved in the pathogenesis of RP [20,30-32].


DNA hypermethylation catalyzed by DNA Methyltransferases (DNMTs) is one important epigenetic factor for RP [33]. DNMTs catalyze the transfer of methyl groups from S-Adenosyl-L-Methionine (SAM) to the 5-position carbon in cytosines within DNA to generate 5-methylcytosine (5mC) [34]. Increased cytosine methylation as well as increased DNMT expression was detected in dying photoreceptors in the rd1, rd2, P23H, and S33ter rodent models for RP [35]. DNA hypermethylation of several individual genes were found in rd1 mice, including important transcription factors YY1, E2F3 and NRL [35]. The transcriptional repression of these target genes contributes to critical dysregulation of cellular events to precipitate photoreceptor cell death [35]. The use of DNMT inhibitor, decitabine, reduced DNA hypermethylation and decreased the number of dying photoreceptors in short term [35], which suggests inhibition of DNA methylation as a potential treatment for RP.


In cellular physiology, Poly-ADP-Ribose Polymerase (PARP) group is the important mediator that facilitates the DNA repair process and strongly protects cells against genotoxic stressors [36,37]. However, excessive PARP activation may overstrain the cellular metabolism, leading to an energetic collapse and followed by cell death [37,38]. In conjunction with its antagonist Poly-ADP-Ribose-Glycohy-Drolase (PARG), free PAR polymers generate. In rd1 mice, free PAR will cause photoreceptors death through nuclear translocation of Apoptosis Inducing Factors (AIF) [39], and oxidative DNA damage related to Transient-Receptor-Potential (TRP) ion channels [40,41]. When PARP-specific inhibitor PJ34 was used in a long-term setting, the number of surviving photoreceptors increased, suggesting a protective effect as well as a possible therapeutic target for RP [42].


Histone Deacetylases (HDACs) regulates the structure of chromatin through deacetylation of histone in neurons [43,44]. There are three main classes of HDAC family, HDAC I (HDAC 1-3 and 8), II (HDAC 4-7, 9, and 10), and III. HDAC hyperactivation would result in significantly altered rd1 gene transcription, including downregulation of the transcription factor CREB [19,45,46]. HDAC4 overexpression prolongs rod survival in rd1 mice, where the survival effect was due to its cytoplasmic activity, and relied partially upon the activity of Hypoxia Inducible Factor 1α (HIF1α) [26]. HIF1α plays a central role in the regulation of oxygen homeostasis [47], and it is not detectable in the mature mouse retina [48]. Exposure of retinas to hypoxia causes stabilization of HIF1α and protects photoreceptors from light-induced retinal degeneration [48]. HIF1α stabilization thus might provide a mechanism for HDAC4-induced photoreceptor protection in rd1 mice [26]. However, experimental evidence also suggested that excessive activation of HDACs I/II promotes cell death [49]. Therefore, the right balance between the activities of different HDAC classes seems to be crucial for cellular viability [49]. Besides, there is cross-talk between HDAC and PARP activity. As mentioned above, PARP is involved in DNA damage repair, while excessive PARP activity may lead to cell death [50]. Increased HDAC activity appeared to be responsible for an activation of PARP in degenerating rd1 photoreceptors [20].


Knocking out Bmi1 results in extensive photoreceptors survival in rd1 retina [51]. CDK4, cyclin-dependent kinase 4, is re-expressed in post-mitotic neurons in various models of neurodegenerative diseases, including Alzheimer’s disease [52,53], Parkinson disease [54], and amyotrophic lateral sclerosis [55]. The re-expression of CDK4 implicates the reentry into the cell cycle and in the transition from G1 to S phase, but fails to complete S phase and undergo apoptosis. In Rd1 mice, the nuclear expression of CDK4 causes the phosphorylation of Rb [51]. Then, E2F1 is released and activated upon Rb phosphorylation and is known to contribute to neuron apoptosis [51]. The upstream epigenetic regulator Bmi1 of CDK4 could promote the apoptosis of neurons and cause the neuron loss in Rd1 retinas by repressing tumor suppressor genes such as Ink4a/Arf locus [51]. Ink4a encodes p16Ink4a, the inhibitor of CDK4 [56]. And Arf encodes p19Arf that could promote expression of p53 [56]. It’s reported that genetic ablation of Bmi1 could provide extensive photoreceptor survival and improvement of retinal function in Rd1 mice [51]. Therefore, Bmi1 and E2f1 could be potential targets for RP gene therapy. Some studies report Bmi1 is involved in DNA repair initiation [57,58]. In Glioblastoma Multiforeme (GBM), an aggressive brain tumor, Bmi1 is enriched in CD133-positive cancer-initiating Neural Stem Cell (NSC) [57]. Bmi1 here prevents NSCs senescence, apoptosis, or differentiation by repression the transcription and activation of tumor suppressor genes [59-65]. Meanwhile, Bmi1 could recruit the DNA damage response machinery to DNA DSB sites in response to radiation, thus promoting NSCs survival [57]. Therefore, Bmi1 may have dual effect on the survival of neural cells.

H3K27me3 and PI3K-Akt

In rd1 retina, pan-trimethyllysine of histone significantly increase, especially histone H3 lysine trimethylation at H3K27 (H3K27me3) [66]. Downregulating H3K27me3 with PCR2 inhibitor DZNep can delay the photoreceptors degeneration in rd1 mice, which is related with multiple signaling pathways, including PI3K-Akt, rod differentiation and calpains [67]. One mechanism of DZNep protective effect is through activating PI3K-Akt pathway [67]. It’s reported that Rd1 retina has high levels of H3K27me3. H3K27me3 is a repressive chromatin mark and mediates epigenetic silencing, which is catalyzed by Ezh2-containing PRC2 [66]. It’s shown that DZNep inhibited Ezh2 protein level, H3k27me3 deposition in ex vivo retinal explants of rd1 mice. Ezh2 is the core part of PRC2, and its HMT enzyme activity could catalyze the addition of methyl groups to H3K27 [67]. Akt could phosphorylate serine 21 on E2h and impedes its binding to H3 [68]. PI3K is the upstream regulator of Akt [67]. Its activation leads to production of PIP3 which recruits Akt to the plasma membrane, where Akt gets phosphorylated and activated pn Thr308 and Ser473 by Pdk1 [69] and mTORC2 [70]. PI3K inhibitor LY294002 had the opposite effect of DZNep on rd1 retinas, which confirmed the role of Akt [67]. When treated with DZNep, the reduced H3K27me3 interacts with PI3K-Akt pathway through de-repressing Pik3r1 and Pik3r3 [67]. Together, Akt-mediated phosphorylation of Ezh2 and H3K27me3-mediated repression of PI3K subunits expression form a negative feedback loop [67]. This network contributes to the photoreceptor survival in rd1 retina. Another possible mechanism is DZNep’s inhibitory effect on photoreceptor genes, Nrl and its downstream target Nr2e3 [67]. Nrl plays an important role in rods differentiation. Precursors that turn on Nrl differentiate into rods and those that do not become cones [71]. CRISPR/Cas9-mediated genome editing targeted on Nrl can protect rod and cone photoreceptors, and restore visual function in mouse RP models [72,73]. Therefore, through down-regulating of Nrl-Nr2e3, DZNep could rescue rods and cones. Calpains are a group of calcium-activated proteases with 14 known isoforms [74], which are strongly activated in degenerating rd1 mouse photoreceptors, in contrast to those of their wt counterparts [75]. DZNep treatment significantly suppressed its elevation in rd1 ex vivo explants, suggesting DZNep can protect rd1 retina by suppressing calpain activity [67].

Treatment for RP

As mentioned at the beginning, present treatments for RP include dietary changes (vitamin A and/or the fish oil docosahexaenoic acid), electronic retinal implants and neuro-protective factors (brain-derived neurotrophic factors [76], basic fibroblast growth factor [77], ciliary neurotrophic factor [78] and others), which have very limited effect [3]. Several gene-specific and mutation-specific treatments are emerging, including RPE65 gene therapy [79-82], REP1 gene for choroideremia [83]. In preclinical studies, gene therapeutics is almost always delivered before the onset of cell degeneration, because these approaches require the presence of the cells that will be targeted [3]. However, most neurodegenerative diseases are diagnosed after the onset of degeneration [84]. Other emerging therapeutic strategies involve Antisense Oligonucleotides (AONs) [85], genome editing using CRISPR/Cas system [86], and cell replacement therapy with retinal progenitor cells or embryonic stem cells [87]. Modifications of histone and DNA are reversible, which makes them good targets for therapeutic intervention. We have already had drugs targeted on the epigenetic machinery such as DNMTs, HDACs. For example, DNMT inhibitors include decitabine, zebularine, while for HDAC inhibitors, we have valproic acid, phenylbutyrate, nicotinamide, AGK2 and so on [33]. But these drugs are mainly designed for stroke, AD, HD or PD. We still do not have any commercial epigenetic-targeting drugs for RP at present. Meanwhile, most of drugs mentioned above are nonspecific. Targeting a specific epigenetic modification rather than affect global modifications would be the possible solution to overcome the off-target effects and the lack of specificity


In summary, we provided a review of the mechanisms of RP pathogenesis, especially the epigenetic modifications. DNA methylation and post-transcriptional histone modifications, including DNMTs, PARP, HDAC4, Bmi1, H3K27me3 and PIK3-Akt pathways, have a great potential for developing novel therapeutic strategies. Besides RP, the past decade has witnessed the accumulation of evidence that collectively points to a role for epigenetic modifications in Huntington’s Disease (HD) [88,89], Parkinson’s Disease (PD) [90], Ataxia-Telangiectasia (AT) [91], and Alzheimer’s Disease (AD) [92]. In this scenario, we saw great potentials for histone modifications in neurodegenerative disease including retinitis pigmentosa.


This study was supported by grants to DC from the National Natural Science Foundation of China (81371022, 81570860, and 81870665).

Competing Financial Interests Statement

The authors declare no competing financial interests.


  1. Pagon RA (1988) Retinitis pigmentosa. SurvOphthalmol 33: 137-177.
  2. Zheng A, Li Y, Tsang SH (2015) Personalized therapeutic strategies for patients with retinitis pigmentosa. Expert Opin Biol Ther 15: 391-402.
  3. Verbakel SK, van Huet RAC, Boon CJF, den Hollander AI, Collin RWJ, et al. (2018) Non-syndromic retinitis pigmentosa. Prog Retin Eye Res 66: 157-186.
  4. Pennings, RJ,Fields RR, Huygen PL, Deutman AF, Kimberling WJ, et al. (2003) Usher syndrome type III can mimic other types of Usher syndrome. Ann OtolRhinolLaryngol 112:525-530.
  5. Tieder M, Levy M, Gubler MC, Gagnadoux MF, Broyer M, et al. (1982) Renal abnormalities in the Bardet-Biedl syndrome. Int J PediatrNephrol 3: 199-203.
  6. Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA, et al. (1999) New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet 36: 437-446.
  7. Grant CA, Berson EL (2001) Treatable forms of retinitis pigmentosa associated with systemic neurological disorders. Int Ophthalmol Clin 41: 103-110.
  8. Berson EL,Rosner B, Sandberg MA, Hayes KC, Nicholson BW, et al. (1993) A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol 111: 761-772.
  9. Berson EL,Rosner B, Sandberg MA, Weigel-DiFranco C, Brockhurst RJ, et al. (2010) Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A. Arch Ophthalmol 128: 403-411.
  10. Zein WM, Jeffrey BG, Wiley HE, Turriff AE, Tumminia SJ, et al. (2014) CNGB3-achromatopsia clinical trial with CNTF: diminished rod pathway responses with no evidence of improvement in cone function. Invest Ophthalmol Vis Sci 55: 6301-6308.
  11. Ahuja AK,Dorn JD, Caspi A, McMahon MJ, Dagnelie G, et al. (2011) Blind subjects implanted with the Argus II retinal prosthesis are able to improve performance in a spatial-motor task. Br J Ophthalmol 95: 539-543.
  12. Dorn JD, Ahuja AK, Caspi A, da Cruz L, Dagnelie G, et al. (2013) The Detection of Motion by Blind Subjects with the Epiretinal 60-Electrode (Argus II) Retinal Prosthesis. JAMA Ophthalmol 131: 183-189.
  13. Bowes C, Li T, Danciger M, Baxter LC, Applebury ML, et al. (1990) Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase. Nature 347: 677-680.
  14. McLaughlin ME, Ehrhart TL, Berson EL, Dryja TP (1995) Mutation spectrum of the gene encoding the beta subunit of rod phosphodiesterase among patients with autosomal recessive retinitis pigmentosa. Proc Natl Acad Sci USA 92: 3249-3253.
  15. Farber DB, Lolley RN (1974) Cyclic guanosine monophosphate: elevation in degenerating photoreceptor cells of the C3H mouse retina. Science 186: 449-451.
  16. Paquet-Durand F, Hauck SM, van Veen T, Ueffing M, Ekstrom P (2009) PKG activity causes photoreceptor cell death in two retinitis pigmentosa models. J Neurochem 108: 796-810.
  17. Arango-Gonzalez B, Trifunovi? D,  Sahaboglu A, Kranz K, Michalakis S, et al. (2014) Identification of a common non-apoptotic cell death mechanism in hereditary retinal degeneration. PLoS One 9: 112142.
  18. SchönC, Paquet-Durand F, Michalakis S (2016) Cav1.4 L-Type Calcium Channels Contribute to Calpain Activation in Degenerating Photoreceptors of rd1 Mice. PLoS One 11: 0156974.
  19. Paquet-Durand F, Azadi S, Hauck SM, Ueffing M, van Veen T, et al. (2006) Calpain is activated in degenerating photoreceptors in the rd1 mouse. J Neurochem 96: 802-814.
  20. Sancho-Pelluz J, Alavi MV, Sahaboglu A, Kustermann S, Farinelli P, et al. (2010) Excessive HDAC activation is critical for neurodegeneration in the rd1 mouse. Cell Death Dis 1: 24.
  21. Wahlin KJ, Enke RA, Fuller JA, Kalesnykas G, Zack DJ, et al. (2013) Epigenetics and cell death: DNA hypermethylation in programmed retinal cell death. PLoS One 8: 79140.
  22. Daiger SP, Sullivan LS, Bowne SJ (2013) Genes and mutations causing retinitis pigmentosa. Clin Genet 84: 132-141.
  23. Daiger SP (2018) The Retinal Information Network; Summaries of genes and loci causing retinal diseases 2.
  24. Waddington CH (2012) The epigenotype, 1942. Int J Epidemiol 41: 10-13.
  25. Cardillo JA, Stout JT, LaBree L, Azen SP, Omphroy L, et al. (1997) Post-traumatic proliferative vitreoretinopathy. The epidemiologic profile, onset, risk factors, and visual outcome. Ophthalmology 104: 1166-1173.
  26. Chen B, Cepko CL (2009) HDAC4 regulates neuronal survival in normal and diseased retinas. Science 323: 256-259.
  27. Blasiak J, Salminen A, Kaarniranta K (2013) Potential of epigenetic mechanisms in AMD pathology. Front Biosci (Schol Ed) 5: 412-425.
  28. Reddy MA, Zhang E, Natarajan R (2015) Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 58: 443-455.
  29. Singh U, Malik MA, Goswami S, Shukla S, Kaur J (2016) Epigenetic regulation of human retinoblastoma. TumourBiol 37: 14427-14441.
  30. Farinelli P, Perera A, Arango-Gonzalez B, Trifunovic D, Wagner M, et al.(2014) DNA methylation and differential gene regulation in photoreceptor cell death. Cell Death Dis 5: 1558.
  31. Chen B, Cepko CL (2009) HDAC4 regulates neuronal survival in normal and diseased retinas.Science 323: 256-259.
  32. Guo, X, Wang SB, Xu H, Ribic A, Mohns EJ, et al. (2015) A short N-terminal domain of HDAC4 preserves photoreceptors and restores visual function in retinitis pigmentosa. Nat Commun 6: 8005.
  33. Hwang JY, Aromolaran KA, Zukin RS (2017) The emerging field of epigenetics in neurodegeneration and neuroprotection. Nat Rev Neurosci 18: 347-361.
  34. Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16: 6-21.
  35. Farinelli P, Perera A, Arango-Gonzalez B, Trifunovic D, Wagner M (2014) DNA methylation and differential gene regulation in photoreceptor cell death.Cell Death Dis 5: 1558.
  36. Schreiber V, Amé JC, Dollé P, Schultz I, Rinaldi B, et al. (2002) Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 277: 23028-23036.
  37. Sims JL, Berger SJ, Berger NA (1983) Poly(ADP-ribose) Polymerase inhibitors preserve nicotinamide adenine dinucleotide and adenosine 5'-triphosphate pools in DNA-damaged cells: mechanism of stimulation of unscheduled DNA synthesis. Biochemistry 22: 5188-5194.
  38. Du L, Zhang X, Han YY, Burke NA, Kochanek PM, et al. (2003) Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress. J Biol Chem 278: 18426-18433.
  39. Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, et al. (2006) Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci USA 103: 18308-18313.
  40. Kraft R, Grimm C, Grosse K, Hoffmann A, Sauerbruch S, et al. (2004) Hydrogen peroxide and ADP-ribose induce TRPM2-mediated calcium influx and cation currents in microglia. Am J Physiol Cell Physiol 286: 129-137.
  41. Buelow B, Song Y, Scharenberg AM (2008) The Poly(ADP-ribose) polymerase PARP-1 is required for oxidative stress-induced TRPM2 activation in lymphocytes. J Biol Chem 283: 24571-24583.
  42. Paquet-Durand F, Silva J, Talukdar T, Johnson LE, Azadi S, et al. (2007) Excessive activation of poly(ADP-ribose) polymerase contributes to inherited photoreceptor degeneration in the retinal degeneration 1 mouse. J Neurosci 27: 10311-10319.
  43. Yang XJ, Seto E (2007) HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 26: 5310-5318.
  44. Bolger TA, Yao TP (2005) Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death. J Neurosci 25: 9544-9553.
  45. Azadi S, Paquet-Durand F, Medstrand P, van VeenT, Ekstrom PA (2006) Up-regulation and increased phosphorylation of Protein Kinase C (PKC) delta, mu and theta in the degenerating rd1 mouse retina. Mol Cell Neurosci 31: 759-773.
  46. Pilz RB, Broderick KE (2005) Role of cyclic GMP in gene regulation. Front Biosci 10: 1239-1268.
  47. Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J ApplPhysiol (1985) 88: 1474-1480.
  48. Grimm C, Wenzel A, Groszer M, Mayser H, Seeliger M, et al. (2002) HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med 8: 718-724.
  49. Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10: 32-42.
  50. Schreiber V, Dantzer F, Ame JC, de Murcia G (2006) Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7: 517-528.
  51. Zencak D, Schouwey K, Chen D, Ekström P, Tanger E, et al. (2013) Retinal degeneration depends on Bmi1 function and reactivation of cell cycle proteins. Proc Natl Acad Sci USA 110: 593-601.
  52. Vincent I, Rosado M, Davies P (1996) Mitotic mechanisms in Alzheimer’s disease? J Cell Biol 132: 413-425.
  53. YangY, Geldmacher DS, Herrup K (2001) DNA replication precedes neuronal cell death in Alzheimer’s disease. J Neurosci 21: 2661-2668.
  54. Hoglinger GU, Breunig JJ, Depboylu C, Rouaux C, Michel PP, et al. (2007) The pRb/E2F cell-cycle pathway mediates cell death in Parkinson’s disease. Proc Natl Acad Sci USA 104: 3585-3590.
  55. Nguyen MD, Boudreau M, Kriz J, Couillard-Després S, Kaplan DR, et al. (2003) Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1. J Neurosci 23: 2131-2140.
  56. Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M, et al. (1999) The oncogene and Polycomb-group gene Bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397: 164-168.
  57. Facchino S, Abdouh M, Chatoo W, Bernier G (2010) BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. J Neurosci 30: 10096-10111.
  58. Ismail IH, Andrin C, McDonald D, Hendzel MJ (2010) BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair. J Cell Biol 191: 45-60.
  59. Lessard J, Sauvageau G (2003) Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423: 255-260.
  60. Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, et al. (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425: 962-967.
  61. Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R (2005) Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev 19: 1432-1437.
  62. Park IK, Qian D, Kiel M, Becker MW, Pihalja M, et al. (2003) Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423: 302-305.
  63. Bruggeman SW, Valk-Lingbeek ME, van der Stoop PP, Jacobs JJ, Kieboom K, et al. (2005) Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes Dev 19: 1438-1443.
  64. Fasano CA, Dimos JT, Ivanova NB, Lowry N, Lemischka IR, et al. (2007) shRNA knockdown of Bmi-1 reveals a critical role for p21-Rb pathway in NSC self-renewal during development. Cell Stem Cell 1: 87-99.
  65. Abdouh M, Facchino S, Chatoo W, Balasingam V, Ferreira J, et al. (2009) BMI1 sustains human glioblastoma multiforme stem cell renewal. J Neurosci 29: 8884-8896.
  66. Margueron R, Reinberg D (2001) The Polycomb complex PRC2 and its mark in life. Nature 469: 343-349.
  67. Zheng S, Xiao L, Liu Y, Wang Y, Cheng L, et al. (2018) DZNep inhibits H3K27me3 deposition and delays retinal degeneration in the rd1 mice. Cell Death Dis 9: 310.
  68. Cha TL, Zhou BP, Xia W, Wu Y, Yang CC, et al. (2005) Akt-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science 310: 306-310.
  69. Mora A, Komander D, van Aalten DM, Alessi DR (2004) PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol 15: 161-170.
  70. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12: 21-35.
  71. Mears AJ, Kondo M, Swain PK, Takada Y, Bush RA, et al. (2001) Nrl is required for rod photoreceptor development. Nat Genet 29: 447-452.
  72. Yu W, Mookherjee S, Chaitankar V, Hiriyanna S, Kim J, et al. (2017) Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice. Nat Commun 8: 14716.
  73. Zhu J, Ming C, Fu X, Duan Y, Hoang DA, et al. (2017) Gene and mutation independent therapy via CRISPR-Cas9 mediated cellular reprogramming in rod photoreceptors. Cell Res 27: 830-833.
  74. Suzuki K, Hata S, Kawabata Y, Sorimachi H (2004) Structure, activation, and biology of calpain. Diabetes 53: 12-18.
  75. Sancho-Pelluz J, Arango-Gonzalez B, Kustermann S, Romero FJ, van Veen T, et al. (2008) Photoreceptor cell death mechanisms in inherited retinal degeneration. MolNeurobiol 38: 253-269.
  76. Okoye G, Zimmer J, Sung J, Gehlbach P, Deering T, et al. (2003) Increased expression of brain-derived neurotrophic factor preserves retinal function and slows cell death from rhodopsin mutation or oxidative damage. J Neurosci 23: 4164-4172.
  77. Faktorovich EG, Steinberg RH, Yasumura D, Matthes MT, LaVail MM (1990) Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor. Nature 347: 83-86.
  78. Liang FQ, Aleman TS, Dejneka NS, Dudus L, Fisher KJ, et al. (2001) Long-term protection of retinal structure but not function using RAAV.CNTF in animal models of retinitis pigmentosa. Mol Ther 4: 461-472.
  79. Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, et al. (2008) Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 358: 2231-2239.
  80. Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, et al. (2008) Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther 19: 979-990.
  81. Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, et al. (2008) Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 358: 2240-2248.
  82. Maguire AM, High KA, Auricchio A, Wright JF, Pierce EA, et al. (2009) Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet 374: 1597-1605.
  83. MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, et al. (2014) Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 383: 1129-1137.
  84. MitamuraY, Mitamura-Aizawa S, Nagasawa T, Katome T, Eguchi H, et al. (2012) Diagnostic imaging in patients with retinitis pigmentosa. J Med Invest 59: 1-11.
  85. Collin RW, Garanto A (2017) Applications of antisense oligonucleotides for the treatment of inherited retinal diseases. Curr Opin Ophthalmol 28: 260-266.
  86. Yanik M, Müller B, Song F, Gall J, Wagner F, et al. (2017) In vivo genome editing as a potential treatment strategy for inherited retinal dystrophies. Prog Retin Eye Res 56: 1-18.
  87. Tang Z, Zhang Y, Wang Y, Zhang D, Shen B, et al. (2017) Progress of stem/progenitor cell-based therapy for retinal degeneration. J Transl Med 15: 99.
  88. Zuccato C, Belyaev N, Conforti P, Ooi L, Tartari M, et al. (2007) Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington’s disease. J Neurosci 27: 6972-6983.
  89. Packer AN, Xing Y, Harper SQ, Jones L, Davidson BL (2008) The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington’s disease. J Neurosci 28: 14341-14346.
  90. Yu M, Suo H, Liu M, Cai L, Liu J, et al. (2013) NRSF/REST neuronal deficient mice are more vulnerable to the neurotoxin MPTP. Neurobiol Aging 34: 916-927.
  91. Li J, Hart RP, Mallimo EM, Swerdel MR, Kusnecov AW, et al. (2013) EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia. Nat Neurosci 16: 1745-1753.
  92. Lu T, Aron L, Zullo J, Pan Y, Kim H, et al. (2014) REST and stress resistance in ageing and Alzheimer’s disease. Nature 507: 448-454.
Ocimum Scientific Publishers

This work is licensed under a Creative Commons Attribution 4.0 International License.  Creative Commons License

Copyright © 2019 - All Rights Reserved -