Epigenetics of diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

 LiuHenan , LiXun , LuYan , ChenXiaolong

Department of Ophthalmology, Shengjing Hospital, China Medical University, Shenyang 110004, China;

Corresponding author：

LiuHenan, Email: liuhn@sj-hospital.org

Keywords：

Diabetic retinopathy/genetics; Epigenesis, genetic; Review

DOI：

10.3760/cma.j.issn.1005-1015.2016.02.027

Video：

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Epigenetic mechanisms influence gene expression and function without modification of the base sequence of DNA and may generateagenetic phenotype. Epigenetic modifications include DNA methylation, histone modifications, and deployment of noncoding RNA. There is growing evidence that epigenetic mechanisms could playacrucial role in the development of diabetic retinopathy (DR). Molecular biological methods which could maintain mitochondrial homeostasis through the regulation of epigenetic mechanisms may prevent the development of DR. Epigenetic-related treatment modalities will become the new direction of targeted therapy for DR.

Citation： LiuHenan, LiXun, LuYan, ChenXiaolong. Epigenetics of diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2016, 32(2): 218-221. doi: 10.3760/cma.j.issn.1005-1015.2016.02.027 Copy

1.	Cunha-Vaz J, Ribeiro L, Lobo C. Phenotypes and biomarkers of diabetic retinopathy[J]. Prog Retin Eye Res,2014, 41:90-111. DOI: 10.1016/j.preteyeres.2014.03.003.
2.	He S, Li X, Chan N, et al. Review: epigenetic mechanisms in ocular disease[J]. Mol Vis, 2013, 19:665-674.
3.	Waddington CH. Der epigenotypus[J]. Endeavour, 1942, 1:18-20.
4.	Holliday R. The inheritance of epigenetic defects[J]. Science, 1987, 238(4824):163-170.
5.	Bonasio R, Tu S, Reinberg D. Molecular signals of epigenetic states[J]. Science, 2010, 330(6004):612-616. DOI:10.1126/science.1191078.
6.	Feng S, Jacobsen SE, Reik W. Epigenetic reprogramming in plant and animal development[J]. Science, 2010, 330(6004):622-627. DOI:10.1126/science.1190614.
7.	Rupp RA, Becker PB. Gene regulation by histone H1: new links to DNA methylation[J]. Cell, 2005, 123(7):1178-1179.
8.	Law JA, Jacobsen SE. Molecular biology: dynamic DNA methylation[J]. Science, 2009, 323(5921):1568-1569. DOI: 10.1126/science.1172782.
9.	Cheung P, Allis CD, Sassone-Corsi P. Signaling to chromatin through histone modifications[J]. Cell, 2000, 103(2):263-271.
10.	Vidanes GM, Bonilla CY, Toczyski DP. Complicated tails: histone modifications and the DNA damage response[J]. Cell, 2005, 121(7):973-976.
11.	Suganuma T, Workman JL. Crosstalk among histone modifications[J]. Cell, 2008, 135(4):604-607. DOI: 10.1016/j.cell.2008.10.036.
12.	Ren B. Transcription: enhancers make non-coding RNA[J]. Nature, 2010, 465(7295):173-174. DOI:10.1038/465173a.
13.	Cech TR, Steitz JA. The noncoding RNA revolution-trashing old rules to forge new ones[J]. Cell, 2014, 157(1):77-94. DOI: 10.1016/j.cell.2014.03.008.
14.	Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function[J]. Cell, 2004, 116(2):281-297.
15.	Chitwood DH, Timmermans MC. Small RNAs are on the move[J]. Nature, 2010, 467(7314):415-419. DOI: 10.1038/nature09351.
16.	Beltrami C, Angelini TG, Emanueli C. Noncoding RNAs in diabetes vascular complications[J].JMol Cell Cardiol, 2015, 89(Pt A):42-50. DOI:10.1016/j.yjmcc.2014.12.014.
17.	Knoll M, Lodish HF, Sun L. Long non-coding RNAs as regulators of the endocrine system[J]. Nat Rev Endocrinol, 2015, 11(3):151-160. DOI:10.1038/nrendo.2014.229.
18.	Tewari S, Zhong Q, Santos JM, et al. Mitochondria DNA replication and DNA methylation in the metabolic memory associated with continued progression of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2012, 53(8):4881-4888. DOI: 10.1167/iovs.12-9732.
19.	Maghbooli Z, Hossein-nezhad A, Larijani B, et al. Global DNA methylation asapossible biomarker for diabetic retinopathy[J]. Diabetes Metab Res Rev, 2015, 31(2):183-189. DOI: 10.1002/dmrr.2584.
20.	Maghbooli Z, Larijani B, Emamgholipour S, et al. Aberrant DNA methylation patterns in diabetic nephropathy[J].JDiabetes Metab Disord, 2014, 13:69. DOI:10.1186/2251-6581-13-69.
21.	Niu PP, Cao Y, Gong T, et al. Hypermethylation of DDAH2 promoter contributes to the dysfunction of endothelial progenitor cells in coronary artery disease patients[J].JTransl Med, 2014, 12:170. DOI:10.1186/1479-5876-12-170.
22.	Syreeni A, El-Osta A, Forsblom C, et al. Genetic examination of SETD7 and SUV39H1/H2 methyltransferases and the risk of diabetes complications in patients with type 1 diabetes[J]. Diabetes, 2011, 60(11):3073-3080. DOI:10.2337/db11-0073.
23.	El-Osta A, Brasacchio D, Yao D, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia[J].JExp Med, 2008, 205(10):2409-2417. DOI:10.1084/jem.20081188.
24.	Romeo G, Liu WH, Asnaghi V, et al. Activation of nuclear factor-kappaB induced by diabetes and high glucose regulatesaproapoptotic program in retinal pericytes[J]. Diabetes, 2002, 51(7):2241-2248.
25.	Mishra M, Zhong Q, Kowluru RA. Epigenetic modifications of Nrf2-mediated glutamate-cysteine ligase: implications for the development of diabetic retinopathy and the metabolic memory phenomenon associated with its continued progression[J]. Free Radic Biol Med, 2014, 75:129-139. DOI:10.1016/j.freeradbiomed.2014.07.001.
26.	Mishra M, Zhong Q, Kowluru RA. Epigenetic modifications of Keap1 regulate its interaction with the protective factor Nrf2 in the development of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2014, 55(11):7256-7265. DOI: 10.1167/iovs.14-15193.
27.	Zhong Q, Kowluru RA. Epigenetic changes in mitochondrial superoxide dismutase in the retina and the development of diabetic retinopathy[J]. Diabetes, 2011, 60(4):1304-1313. DOI: 10.2337/db10-0133.
28.	Zhong Q, Kowluru RA. Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon[J].JCell Biochem, 2010, 110(6):1306-1313. DOI: 10.1002/jcb.22644.
29.	Kowluru RA, Zhong Q, Kanwar M. Metabolic memory and diabetic retinopathy: role of inflammatory mediators in retinal pericytes[J]. Exp Eye Res, 2010, 90(5):617-623. DOI: 10.1016/j.exer.2010.02.006.
30.	Zhong Q, Kowluru RA. Epigenetic modification of Sod2 in the development of diabetic retinopathy and in the metabolic memory: role of histone methylation[J]. Invest Ophthalmol Vis Sci, 2013, 54(1):244-250. DOI: 10.1167/iovs.12-10854.
31.	Kadiyala CS, Zheng L, Du Y, et al. Acetylation of retinal histones in diabetes increases inflammatory proteins: effects of minocycline and manipulation of histone acetyltransferase (HAT) and histone deacetylase (HDAC)[J].JBiol Chem, 2012, 287(31):25869-25880. DOI: 10.1074/jbc.M112.375204.
32.	Zhong Q, Kowluru RA. Regulation of matrix metalloproteinase-9 by epigenetic modifications and the development of diabetic retinopathy[J]. Diabetes, 2013, 62(7):2559-2568. DOI: 10.2337/db12-1141.
33.	Perrone L, Devi TS, Hosoya K, et al. Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditions[J].JCell Physiol, 2009, 221(1):262-272. DOI: 10.1002/jcp.21852.
34.	Xu S. microRNA expression in the eyes and their significance in relation to functions[J]. Prog Retin Eye Res, 2009, 28(2):87-116. DOI: 10.1016/j.preteyeres.2008.11.003.
35.	Ryan DG, Oliveira-Fernandes M, Lavker RM. MicroRNAs of the mammalian eye display distinct and overlapping tissue specificity[J]. Mol Vis, 2006, 12:1175-1184.
36.	Xu S, Witmer PD, Lumayag S, et al. MicroRNA (miRNA) transcriptome of mouse retina and identification ofasensory organ-specific miRNA cluster[J].JBiol Chem, 2007, 282(34):25053-25066.
37.	Loscher CJ, Hokamp K, Kenna PF, et al. Altered retinal microRNA expression profile inamouse model of retinitis pigmentosa[J]. Genome Biol, 2007, 8(11):R248. DOI:10.1186/gb-2007-8-11-r248.
38.	Karali M, Peluso I, Gennarino VA, et al. miRNeye:amicroRNA expression atlas of the mouse eye[J]. BMC Genomics, 2010,11:715. DOI: 10.1186/1471-2164-11-715.
39.	McArthur K, Feng B, Wu Y, et al. MicroRNA-200b regulates vascular endothelial growth factor-mediated alterations in diabetic retinopathy[J]. Diabetes, 2011, 60(4):1314-1323. DOI: 10.2337/db10-1557.
40.	Kovacs B, Lumayag S, Cowan C, et al. MicroRNAs in early diabetic retinopathy in streptozotocin-induced diabetic rats[J]. Invest Ophthalmol Vis Sci, 2011, 52(7):4402-4409. DOI: 10.1167/iovs.10-6879.
41.	Suárez Y, Fernández-Hernando C, Yu J, et al. Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis[J]. Proc Natl Acad Sci USA, 2008, 105(37):14082-14087. DOI: 10.1073/pnas.0804597105.
42.	Wu JH, Gao Y, Ren AJ, et al. Altered microRNA expression profiles in retinas with diabetic retinopathy[J]. Ophthalmic Res, 2012, 47(4):195-201. DOI: 10.1159/000331992.
43.	Murray AR, Chen Q, Takahashi Y, et al. MicroRNA-200b downregulates oxidation resistance 1 (Oxr1) expression in the retina of type 1 diabetes model[J]. Invest Ophthalmol Vis Sci, 2013, 54(3):1689-1697. DOI: 10.1167/iovs.12-10921.
44.	Barber AJ, Gardner TW, Abcouwer SF. The significance of vascular and neural apoptosis to the pathology of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2011, 52(2):1156-1163. DOI: 10.1167/iovs.10-6293.
45.	Yan B, Tao ZF, Li XM, et al. Aberrant expression of long noncoding RNAs in early diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2014, 55(2):941-951. DOI: 10.1167/iovs.13-13221.
46.	Liu JY, Yao J, Li XM, et al. Pathogenic role of lncRNA-MALAT1 in endothelial cell dysfunction in diabetes mellitus[J]. Cell Death Dis, 2014, 5:1506. DOI: 10.1038/cddis.2014.466.
47.	Yan B, Yao J, Liu JY, et al. lncRNA-MIAT regulates microvascular dysfunction by functioning asacompeting endogenous RNA[J]. Circ Res, 2015, 116(7):1143-1156. DOI: 10.1161/CIRCRESAHA.116.305510.
48.	Jaé N, Dimmeler S. Long noncoding RNAs in diabetic retinopathy[J]. Circ Res, 2015, 116(7):1104-1106. DOI:10.1161/CIRCRESAHA.115.306051.

1. Cunha-Vaz J, Ribeiro L, Lobo C. Phenotypes and biomarkers of diabetic retinopathy[J]. Prog Retin Eye Res,2014, 41:90-111. DOI: 10.1016/j.preteyeres.2014.03.003.
2. He S, Li X, Chan N, et al. Review: epigenetic mechanisms in ocular disease[J]. Mol Vis, 2013, 19:665-674.
3. Waddington CH. Der epigenotypus[J]. Endeavour, 1942, 1:18-20.
4. Holliday R. The inheritance of epigenetic defects[J]. Science, 1987, 238(4824):163-170.
5. Bonasio R, Tu S, Reinberg D. Molecular signals of epigenetic states[J]. Science, 2010, 330(6004):612-616. DOI:10.1126/science.1191078.
6. Feng S, Jacobsen SE, Reik W. Epigenetic reprogramming in plant and animal development[J]. Science, 2010, 330(6004):622-627. DOI:10.1126/science.1190614.
7. Rupp RA, Becker PB. Gene regulation by histone H1: new links to DNA methylation[J]. Cell, 2005, 123(7):1178-1179.
8. Law JA, Jacobsen SE. Molecular biology: dynamic DNA methylation[J]. Science, 2009, 323(5921):1568-1569. DOI: 10.1126/science.1172782.
9. Cheung P, Allis CD, Sassone-Corsi P. Signaling to chromatin through histone modifications[J]. Cell, 2000, 103(2):263-271.
10. Vidanes GM, Bonilla CY, Toczyski DP. Complicated tails: histone modifications and the DNA damage response[J]. Cell, 2005, 121(7):973-976.
11. Suganuma T, Workman JL. Crosstalk among histone modifications[J]. Cell, 2008, 135(4):604-607. DOI: 10.1016/j.cell.2008.10.036.
12. Ren B. Transcription: enhancers make non-coding RNA[J]. Nature, 2010, 465(7295):173-174. DOI:10.1038/465173a.
13. Cech TR, Steitz JA. The noncoding RNA revolution-trashing old rules to forge new ones[J]. Cell, 2014, 157(1):77-94. DOI: 10.1016/j.cell.2014.03.008.
14. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function[J]. Cell, 2004, 116(2):281-297.
15. Chitwood DH, Timmermans MC. Small RNAs are on the move[J]. Nature, 2010, 467(7314):415-419. DOI: 10.1038/nature09351.
16. Beltrami C, Angelini TG, Emanueli C. Noncoding RNAs in diabetes vascular complications[J].JMol Cell Cardiol, 2015, 89(Pt A):42-50. DOI:10.1016/j.yjmcc.2014.12.014.
17. Knoll M, Lodish HF, Sun L. Long non-coding RNAs as regulators of the endocrine system[J]. Nat Rev Endocrinol, 2015, 11(3):151-160. DOI:10.1038/nrendo.2014.229.
18. Tewari S, Zhong Q, Santos JM, et al. Mitochondria DNA replication and DNA methylation in the metabolic memory associated with continued progression of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2012, 53(8):4881-4888. DOI: 10.1167/iovs.12-9732.
19. Maghbooli Z, Hossein-nezhad A, Larijani B, et al. Global DNA methylation asapossible biomarker for diabetic retinopathy[J]. Diabetes Metab Res Rev, 2015, 31(2):183-189. DOI: 10.1002/dmrr.2584.
20. Maghbooli Z, Larijani B, Emamgholipour S, et al. Aberrant DNA methylation patterns in diabetic nephropathy[J].JDiabetes Metab Disord, 2014, 13:69. DOI:10.1186/2251-6581-13-69.
21. Niu PP, Cao Y, Gong T, et al. Hypermethylation of DDAH2 promoter contributes to the dysfunction of endothelial progenitor cells in coronary artery disease patients[J].JTransl Med, 2014, 12:170. DOI:10.1186/1479-5876-12-170.
22. Syreeni A, El-Osta A, Forsblom C, et al. Genetic examination of SETD7 and SUV39H1/H2 methyltransferases and the risk of diabetes complications in patients with type 1 diabetes[J]. Diabetes, 2011, 60(11):3073-3080. DOI:10.2337/db11-0073.
23. El-Osta A, Brasacchio D, Yao D, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia[J].JExp Med, 2008, 205(10):2409-2417. DOI:10.1084/jem.20081188.
24. Romeo G, Liu WH, Asnaghi V, et al. Activation of nuclear factor-kappaB induced by diabetes and high glucose regulatesaproapoptotic program in retinal pericytes[J]. Diabetes, 2002, 51(7):2241-2248.
25. Mishra M, Zhong Q, Kowluru RA. Epigenetic modifications of Nrf2-mediated glutamate-cysteine ligase: implications for the development of diabetic retinopathy and the metabolic memory phenomenon associated with its continued progression[J]. Free Radic Biol Med, 2014, 75:129-139. DOI:10.1016/j.freeradbiomed.2014.07.001.
26. Mishra M, Zhong Q, Kowluru RA. Epigenetic modifications of Keap1 regulate its interaction with the protective factor Nrf2 in the development of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2014, 55(11):7256-7265. DOI: 10.1167/iovs.14-15193.
27. Zhong Q, Kowluru RA. Epigenetic changes in mitochondrial superoxide dismutase in the retina and the development of diabetic retinopathy[J]. Diabetes, 2011, 60(4):1304-1313. DOI: 10.2337/db10-0133.
28. Zhong Q, Kowluru RA. Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon[J].JCell Biochem, 2010, 110(6):1306-1313. DOI: 10.1002/jcb.22644.
29. Kowluru RA, Zhong Q, Kanwar M. Metabolic memory and diabetic retinopathy: role of inflammatory mediators in retinal pericytes[J]. Exp Eye Res, 2010, 90(5):617-623. DOI: 10.1016/j.exer.2010.02.006.
30. Zhong Q, Kowluru RA. Epigenetic modification of Sod2 in the development of diabetic retinopathy and in the metabolic memory: role of histone methylation[J]. Invest Ophthalmol Vis Sci, 2013, 54(1):244-250. DOI: 10.1167/iovs.12-10854.
31. Kadiyala CS, Zheng L, Du Y, et al. Acetylation of retinal histones in diabetes increases inflammatory proteins: effects of minocycline and manipulation of histone acetyltransferase (HAT) and histone deacetylase (HDAC)[J].JBiol Chem, 2012, 287(31):25869-25880. DOI: 10.1074/jbc.M112.375204.
32. Zhong Q, Kowluru RA. Regulation of matrix metalloproteinase-9 by epigenetic modifications and the development of diabetic retinopathy[J]. Diabetes, 2013, 62(7):2559-2568. DOI: 10.2337/db12-1141.
33. Perrone L, Devi TS, Hosoya K, et al. Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditions[J].JCell Physiol, 2009, 221(1):262-272. DOI: 10.1002/jcp.21852.
34. Xu S. microRNA expression in the eyes and their significance in relation to functions[J]. Prog Retin Eye Res, 2009, 28(2):87-116. DOI: 10.1016/j.preteyeres.2008.11.003.
35. Ryan DG, Oliveira-Fernandes M, Lavker RM. MicroRNAs of the mammalian eye display distinct and overlapping tissue specificity[J]. Mol Vis, 2006, 12:1175-1184.
36. Xu S, Witmer PD, Lumayag S, et al. MicroRNA (miRNA) transcriptome of mouse retina and identification ofasensory organ-specific miRNA cluster[J].JBiol Chem, 2007, 282(34):25053-25066.
37. Loscher CJ, Hokamp K, Kenna PF, et al. Altered retinal microRNA expression profile inamouse model of retinitis pigmentosa[J]. Genome Biol, 2007, 8(11):R248. DOI:10.1186/gb-2007-8-11-r248.
38. Karali M, Peluso I, Gennarino VA, et al. miRNeye:amicroRNA expression atlas of the mouse eye[J]. BMC Genomics, 2010,11:715. DOI: 10.1186/1471-2164-11-715.
39. McArthur K, Feng B, Wu Y, et al. MicroRNA-200b regulates vascular endothelial growth factor-mediated alterations in diabetic retinopathy[J]. Diabetes, 2011, 60(4):1314-1323. DOI: 10.2337/db10-1557.
40. Kovacs B, Lumayag S, Cowan C, et al. MicroRNAs in early diabetic retinopathy in streptozotocin-induced diabetic rats[J]. Invest Ophthalmol Vis Sci, 2011, 52(7):4402-4409. DOI: 10.1167/iovs.10-6879.
41. Suárez Y, Fernández-Hernando C, Yu J, et al. Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis[J]. Proc Natl Acad Sci USA, 2008, 105(37):14082-14087. DOI: 10.1073/pnas.0804597105.
42. Wu JH, Gao Y, Ren AJ, et al. Altered microRNA expression profiles in retinas with diabetic retinopathy[J]. Ophthalmic Res, 2012, 47(4):195-201. DOI: 10.1159/000331992.
43. Murray AR, Chen Q, Takahashi Y, et al. MicroRNA-200b downregulates oxidation resistance 1 (Oxr1) expression in the retina of type 1 diabetes model[J]. Invest Ophthalmol Vis Sci, 2013, 54(3):1689-1697. DOI: 10.1167/iovs.12-10921.
44. Barber AJ, Gardner TW, Abcouwer SF. The significance of vascular and neural apoptosis to the pathology of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2011, 52(2):1156-1163. DOI: 10.1167/iovs.10-6293.
45. Yan B, Tao ZF, Li XM, et al. Aberrant expression of long noncoding RNAs in early diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2014, 55(2):941-951. DOI: 10.1167/iovs.13-13221.
46. Liu JY, Yao J, Li XM, et al. Pathogenic role of lncRNA-MALAT1 in endothelial cell dysfunction in diabetes mellitus[J]. Cell Death Dis, 2014, 5:1506. DOI: 10.1038/cddis.2014.466.
47. Yan B, Yao J, Liu JY, et al. lncRNA-MIAT regulates microvascular dysfunction by functioning asacompeting endogenous RNA[J]. Circ Res, 2015, 116(7):1143-1156. DOI: 10.1161/CIRCRESAHA.116.305510.
48. Jaé N, Dimmeler S. Long noncoding RNAs in diabetic retinopathy[J]. Circ Res, 2015, 116(7):1104-1106. DOI:10.1161/CIRCRESAHA.115.306051.

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