Epigenetic research progression in diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Xie Ruotian ,  Yan Hua

Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China;

Corresponding author：

Yan Hua, Email: phuayan2000@163.com

Keywords：

Diabetic retinopathy/genetics; Epigenesis; geneticReview

DOI：

10.3760/cma.j.cn511434-20190213-00045

Video：

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Abstract Full text Figures/Tables Video References Cited by

Epigenetics has become one of the major research directions of human genome after genome sequencing, and plays an important role in many complex pathophysiological processes such as tumor, biological development, aging and neuropathy. The metabolic memory phenomenon in diabetic retinopathy (DR) suggests that the pathogenesis of DR has a complicated relationship with epigenetic factors. Many studies show the changes and roles of histone modification, DNA methylation and non-coding RNA in the development of DR. However, the current understanding of how epigenetic modifications affect diseases is limited, and most studies on histone modifications have not been carried out in DR. There is still a lot of room for development in epigenetic research on DR. At the same time, epigenetic modification is very complicated, and how to integrate the interaction of different modifications in the development stage of DR is the focus of future research work.

Citation： Xie Ruotian, Yan Hua. Epigenetic research progression in diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2020, 36(8): 657-660. doi: 10.3760/cma.j.cn511434-20190213-00045 Copy

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2.	Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group, Lachin JM, Genuth S, et al. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy[J]. N Engl J Med, 2000, 342(6): 381-389. DOI: 10.1056/NEJM200002103420603.
3.	Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease[J]. Nature, 2019, 571(7766): 489-499. DOI: 10.1038/s41586-019-1411-0.
4.	Wu C, Morris JR. Genes, genetics, and epigenetics: a correspondence[J]. Science, 2001, 293(5532): 1103-1105. DOI: 10.1126/science.293.5532.1103.
5.	Li B, Carey M, Workman JL. The role of chromatin during transcription[J]. Cell, 2007, 128(4): 707-719. DOI: 10.1016/j.cell.2007.01.015.
6.	Moore LD, Le T, Fan G. DNA methylation and its basic function[J]. Neuropsychopharmacology, 2013, 38(1): 23-38. DOI: 10.1038/npp.2012.112.
7.	Becker PB, Horz W. ATP-dependent nucleosome remodeling[J]. Annu Rev Biochem, 2002, 71: 247-273. DOI: 10.1146/annurev.biochem.71.110601.135400.
8.	Miao F, Chen Z, Genuth S, et al. Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes[J]. Diabetes, 2014, 63(5): 1748-1762. DOI: 10.2337/db13-1251.
9.	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]. J Biol Chem, 2012, 287(31): 25869-25880. DOI: 10.1074/jbc.M112.375204.
10.	Zhong Q, Kowluru RA. Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon[J]. J Cell Biochem, 2010, 110(6): 1306-1313. DOI: 10.1002/jcb.22644.
11.	Mortuza R, Chen S, Feng B, et al. High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway [J/OL]. PLoS One, 2013, 8(1): 54514[2013-01-16]. https://assays.cancer.gov/CPTAC-1240. DOI: 10.1371/journal.pone.0054514.
12.	Li P, Zhang L, Zhou C, et al. Sirt 1 activator inhibits the AGE-induced apoptosis and p53 acetylation in human vascular endothelial cells[J]. J Toxicol Sci, 2015, 40(5): 615-624. DOI: 10.2131/jts.40.615.
13.	Chang M, Zhang B, Tian Y, et al. AGEs decreased SIRT3 expression and SIRT3 activation protected ages-induced EPCs' dysfunction and strengthened anti-oxidant capacity[J]. Inflammation, 2017, 40(2): 473-485. DOI: 10.1007/s10753-016-0493-1.
14.	Mortuza R, Feng B, Chakrabarti S. SIRT1 reduction causes renal and retinal injury in diabetes through endothelin 1 and transforming growth factor beta1[J]. J Cell Mol Med, 2015, 19(8): 1857-1867. DOI: 10.1111/jcmm.12557.
15.	Wang C, You Q, Cao X, et al. Micro RNA-19a suppresses interleukin-10 in peripheral B cells of patients with diabetic retinopathy[J]. Am J Transl Res, 2017, 9(3): 1410-1417.
16.	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.
17.	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.
18.	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.
19.	Agardh E, Lundstig A, Perfilyev A, et al. Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy[J]. BMC Med, 2015, 13: 182. DOI: 10.1186/s12916-015-0421-5.
20.	Maghbooli Z, Hossein-Nezhad A, Larijani B, et al. Global DNA methylation as a possible biomarker for diabetic retinopathy[J]. Diabetes Metab Res Rev, 2015, 31(2): 183-189. DOI: 10.1002/dmrr.2584.
21.	Mishra M, Kowluru RA. DNA methylation-a potential source of mitochondria DNA base mismatch in the development of diabetic retinopathy[J]. Mol Neurobiol, 2019, 56(1): 88-101. DOI: 10.1007/s12035-018-1086-9.
22.	Duraisamy AJ, Mishra M, Kowluru A, et al. Epigenetics and regulation of oxidative stress in diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2018, 59(12): 4831-4840. DOI: 10.1167/iovs.18-24548.
23.	Kowluru RA. Retinopathy in a diet-induced type 2 diabetic rat model and role of epigenetic modifications[J]. Diabetes, 2020, 69(4): 689-698. DOI: 10.2337/db19-1009.
24.	Mishra M, Kowluru RA. Epigenetic modification of mitochondrial DNA in the development of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2015, 56(9): 5133-5142. DOI: 10.1167/iovs.15-16937.
25.	Mishra M, Kowluru RA. The role of DNA methylation in the metabolic memory phenomenon associated with the continued progression of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2016, 57(13): 5748-5757. DOI: 10.1167/iovs.16-19759.
26.	Kowluru RA, Mohammad G. Epigenetics and mitochondrial stability in the metabolic memory phenomenon associated with continued progression of diabetic retinopathy[J]. Sci Rep, 2020, 10(1): 6655. DOI: 10.1038/s41598-020-63527-1.
27.	Kowluru RA, Shan Y, Mishra M. Dynamic DNA methylation of matrix metalloproteinase-9 in the development of diabetic retinopathy[J]. Lab Invest, 2016, 96(10): 1040-1049. DOI: 10.1038/labinvest.2016.78.
28.	Kowluru RA, Shan Y. Role of oxidative stress in epigenetic modification of MMP-9 promoter in the development of diabetic retinopathy[J]. Graefe's Arch Clin Exp Ophthalmol, 2017, 255(5): 955-962. DOI: 10.1007/s00417-017-3594-0.
29.	Mohammad G, Kowluru RA. Homocysteine disrupts balance between MMP-9 and its tissue inhibitor in diabetic retinopathy: the role of DNA methylation[J]. Int J Mol Sci, 2020, 21(5): 1771. DOI: 10.3390/ijms21051771.
30.	Duraisamy AJ, Mishra M, Kowluru RA. Crosstalk between histone and DNA methylation in regulation of retinal matrix metalloproteinase-9 in diabetes[J]. Invest Ophthalmol Vis Sci, 2017, 58(14): 6440-6448. DOI: 10.1167/iovs.17-22706.
31.	Zampetaki A, Willeit P, Burr S, et al. Angiogenic microRNAs linked to incidence and progression of diabetic retinopathy in type 1 diabetes[J]. Diabetes, 2016, 65(1): 216-227. DOI: 10.2337/db15-0389.
32.	Barutta F, Bruno G, Matullo G, et al. MicroRNA-126 and micro-/macrovascular complications of type 1 diabetes in the EURODIAB Prospective Complications Study[J]. Acta Diabetol, 2017, 54(2): 133-139. DOI: 10.1007/s00592-016-0915-4.
33.	Santos-Bezerra DP, Santos AS, Guimaraes GC, et al. Micro-RNAs 518d-3p and 618 are upregulated in individuals with type 1 diabetes with multiple microvascular complications[J]. Front Endocrinol (Lausanne), 2019, 10: 385. DOI: 10.3389/fendo.2019.00385.
34.	Yan L, Lee S, Lazzaro DR, et al. Single and compound knock-outs of microRNA (miRNA)-155 and its angiogenic gene target ccn1 in mice alter vascular and neovascular growth in the retina via resident microglia[J]. J Biol Chem, 2015, 290(38): 23264-23281. DOI: 10.1074/jbc.M115.646950.
35.	Gong Q, Xie J, Liu Y, et al. Differentially expressed micrornas in the development of early diabetic retinopathy [J/OL]. J Diabetes Res, 2017, 2017: 4727942[2017-06-15]. http://europepmc.org/article/MED/28706953. DOI: 10.1155/2017/4727942.
36.	Yuan Q, Sun T, Ye F, et al. MicroRNA-124-3p affects proliferation, migration and apoptosis of bladder cancer cells through targeting AURKA[J]. Cancer Biomark, 2017, 19(1): 93-101. DOI: 10.3233/CBM-160427.
37.	Jiang Q, Lyu XM, Yuan Y, et al. Plasma miR-21 expression: an indicator for the severity of type 2 diabetes with diabetic retinopathy [J/OL]. Biosci Rep, 2017, 37(2): BSR20160589[2017-04-28]. http://europepmc.org/article/MED/28108673. DOI: 10.1042/BSR20160589.
38.	Lu JM, Zhang ZZ, Ma X, et al. Repression of microRNA-21 inhibits retinal vascular endothelial cell growth and angiogenesis via PTEN dependent-PI3K/Akt/VEGF signaling pathway in diabetic retinopathy [J/OL]. Exp Eye Res, 2020, 190: 107886[2019-11-21]. https://linkinghub.elsevier.com/retrieve/pii/S0014-4835(18)30390-7. DOI: 10.1016/j.exer.2019.107886.
39.	Yan B, Yao J, Liu JY, et al. lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA[J]. Circ Res, 2015, 116(7): 1143-1156. DOI: 10.1161/CIRCRESAHA.116.305510.
40.	Shan K, Liu C, Liu BH, et al. Circular noncoding RNA HIPK3 mediates retinal vascular dysfunction in diabetes mellitus[J]. Circulation, 2017, 136(17): 1629-1642. DOI: 10.1161/CIRCULATIONAHA.117.029004.
41.	Khan M, Walters LL, Li Q, et al. Characterization and pharmacologic targeting of EZH2, a fetal retinal protein and epigenetic regulator, in human retinoblastoma[J]. Lab Invest, 2015, 95(11): 1278-1290. DOI: 10.1038/labinvest.2015.104.
42.	Huether R, Dong L, Chen X, et al. The landscape of somatic mutations in epigenetic regulators across 1, 000 paediatric cancer genomes [J/OL]. Nat Commun, 2014, 5: 3630[2014-04-08]. http://europepmc.org/article/MED/24710217. DOI: 10.1038/ncomms4630.
43.	Choy KW, Pang CP, Yu CB, et al. Loss of heterozygosity and mutations are the major mechanisms of RB1 gene inactivation in Chinese with sporadic retinoblastoma[J]. Hum Mutat, 2002, 20(5): 408. DOI: 10.1002/humu.9077.
44.	Ayari-Jeridi H, Moran K, Chebbi A, et al. Mutation spectrum of RB1 gene in unilateral retinoblastoma cases from Tunisia and correlations with clinical features [J/OL]. PLoS One, 2015, 10(1): 0116615[2015-01-20]. http://europepmc.org/article/MED/25602518. DOI: 10.1371/journal.pone.0116615.
45.	Du J, Johnson LM, Jacobsen SE, et al. DNA methylation pathways and their crosstalk with histone methylation[J]. Nat Rev Mol Cell Biol, 2015, 16(9): 519-532. DOI: 10.1038/nrm4043.

1. Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus[J]. N Engl J Med, 1993, 329(14): 977-986. DOI: 10.1056/NEJM199309303291401.
2. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group, Lachin JM, Genuth S, et al. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy[J]. N Engl J Med, 2000, 342(6): 381-389. DOI: 10.1056/NEJM200002103420603.
3. Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease[J]. Nature, 2019, 571(7766): 489-499. DOI: 10.1038/s41586-019-1411-0.
4. Wu C, Morris JR. Genes, genetics, and epigenetics: a correspondence[J]. Science, 2001, 293(5532): 1103-1105. DOI: 10.1126/science.293.5532.1103.
5. Li B, Carey M, Workman JL. The role of chromatin during transcription[J]. Cell, 2007, 128(4): 707-719. DOI: 10.1016/j.cell.2007.01.015.
6. Moore LD, Le T, Fan G. DNA methylation and its basic function[J]. Neuropsychopharmacology, 2013, 38(1): 23-38. DOI: 10.1038/npp.2012.112.
7. Becker PB, Horz W. ATP-dependent nucleosome remodeling[J]. Annu Rev Biochem, 2002, 71: 247-273. DOI: 10.1146/annurev.biochem.71.110601.135400.
8. Miao F, Chen Z, Genuth S, et al. Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes[J]. Diabetes, 2014, 63(5): 1748-1762. DOI: 10.2337/db13-1251.
9. 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]. J Biol Chem, 2012, 287(31): 25869-25880. DOI: 10.1074/jbc.M112.375204.
10. Zhong Q, Kowluru RA. Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon[J]. J Cell Biochem, 2010, 110(6): 1306-1313. DOI: 10.1002/jcb.22644.
11. Mortuza R, Chen S, Feng B, et al. High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway [J/OL]. PLoS One, 2013, 8(1): 54514[2013-01-16]. https://assays.cancer.gov/CPTAC-1240. DOI: 10.1371/journal.pone.0054514.
12. Li P, Zhang L, Zhou C, et al. Sirt 1 activator inhibits the AGE-induced apoptosis and p53 acetylation in human vascular endothelial cells[J]. J Toxicol Sci, 2015, 40(5): 615-624. DOI: 10.2131/jts.40.615.
13. Chang M, Zhang B, Tian Y, et al. AGEs decreased SIRT3 expression and SIRT3 activation protected ages-induced EPCs' dysfunction and strengthened anti-oxidant capacity[J]. Inflammation, 2017, 40(2): 473-485. DOI: 10.1007/s10753-016-0493-1.
14. Mortuza R, Feng B, Chakrabarti S. SIRT1 reduction causes renal and retinal injury in diabetes through endothelin 1 and transforming growth factor beta1[J]. J Cell Mol Med, 2015, 19(8): 1857-1867. DOI: 10.1111/jcmm.12557.
15. Wang C, You Q, Cao X, et al. Micro RNA-19a suppresses interleukin-10 in peripheral B cells of patients with diabetic retinopathy[J]. Am J Transl Res, 2017, 9(3): 1410-1417.
16. 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.
17. 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.
18. 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.
19. Agardh E, Lundstig A, Perfilyev A, et al. Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy[J]. BMC Med, 2015, 13: 182. DOI: 10.1186/s12916-015-0421-5.
20. Maghbooli Z, Hossein-Nezhad A, Larijani B, et al. Global DNA methylation as a possible biomarker for diabetic retinopathy[J]. Diabetes Metab Res Rev, 2015, 31(2): 183-189. DOI: 10.1002/dmrr.2584.
21. Mishra M, Kowluru RA. DNA methylation-a potential source of mitochondria DNA base mismatch in the development of diabetic retinopathy[J]. Mol Neurobiol, 2019, 56(1): 88-101. DOI: 10.1007/s12035-018-1086-9.
22. Duraisamy AJ, Mishra M, Kowluru A, et al. Epigenetics and regulation of oxidative stress in diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2018, 59(12): 4831-4840. DOI: 10.1167/iovs.18-24548.
23. Kowluru RA. Retinopathy in a diet-induced type 2 diabetic rat model and role of epigenetic modifications[J]. Diabetes, 2020, 69(4): 689-698. DOI: 10.2337/db19-1009.
24. Mishra M, Kowluru RA. Epigenetic modification of mitochondrial DNA in the development of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2015, 56(9): 5133-5142. DOI: 10.1167/iovs.15-16937.
25. Mishra M, Kowluru RA. The role of DNA methylation in the metabolic memory phenomenon associated with the continued progression of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2016, 57(13): 5748-5757. DOI: 10.1167/iovs.16-19759.
26. Kowluru RA, Mohammad G. Epigenetics and mitochondrial stability in the metabolic memory phenomenon associated with continued progression of diabetic retinopathy[J]. Sci Rep, 2020, 10(1): 6655. DOI: 10.1038/s41598-020-63527-1.
27. Kowluru RA, Shan Y, Mishra M. Dynamic DNA methylation of matrix metalloproteinase-9 in the development of diabetic retinopathy[J]. Lab Invest, 2016, 96(10): 1040-1049. DOI: 10.1038/labinvest.2016.78.
28. Kowluru RA, Shan Y. Role of oxidative stress in epigenetic modification of MMP-9 promoter in the development of diabetic retinopathy[J]. Graefe's Arch Clin Exp Ophthalmol, 2017, 255(5): 955-962. DOI: 10.1007/s00417-017-3594-0.
29. Mohammad G, Kowluru RA. Homocysteine disrupts balance between MMP-9 and its tissue inhibitor in diabetic retinopathy: the role of DNA methylation[J]. Int J Mol Sci, 2020, 21(5): 1771. DOI: 10.3390/ijms21051771.
30. Duraisamy AJ, Mishra M, Kowluru RA. Crosstalk between histone and DNA methylation in regulation of retinal matrix metalloproteinase-9 in diabetes[J]. Invest Ophthalmol Vis Sci, 2017, 58(14): 6440-6448. DOI: 10.1167/iovs.17-22706.
31. Zampetaki A, Willeit P, Burr S, et al. Angiogenic microRNAs linked to incidence and progression of diabetic retinopathy in type 1 diabetes[J]. Diabetes, 2016, 65(1): 216-227. DOI: 10.2337/db15-0389.
32. Barutta F, Bruno G, Matullo G, et al. MicroRNA-126 and micro-/macrovascular complications of type 1 diabetes in the EURODIAB Prospective Complications Study[J]. Acta Diabetol, 2017, 54(2): 133-139. DOI: 10.1007/s00592-016-0915-4.
33. Santos-Bezerra DP, Santos AS, Guimaraes GC, et al. Micro-RNAs 518d-3p and 618 are upregulated in individuals with type 1 diabetes with multiple microvascular complications[J]. Front Endocrinol (Lausanne), 2019, 10: 385. DOI: 10.3389/fendo.2019.00385.
34. Yan L, Lee S, Lazzaro DR, et al. Single and compound knock-outs of microRNA (miRNA)-155 and its angiogenic gene target ccn1 in mice alter vascular and neovascular growth in the retina via resident microglia[J]. J Biol Chem, 2015, 290(38): 23264-23281. DOI: 10.1074/jbc.M115.646950.
35. Gong Q, Xie J, Liu Y, et al. Differentially expressed micrornas in the development of early diabetic retinopathy [J/OL]. J Diabetes Res, 2017, 2017: 4727942[2017-06-15]. http://europepmc.org/article/MED/28706953. DOI: 10.1155/2017/4727942.
36. Yuan Q, Sun T, Ye F, et al. MicroRNA-124-3p affects proliferation, migration and apoptosis of bladder cancer cells through targeting AURKA[J]. Cancer Biomark, 2017, 19(1): 93-101. DOI: 10.3233/CBM-160427.
37. Jiang Q, Lyu XM, Yuan Y, et al. Plasma miR-21 expression: an indicator for the severity of type 2 diabetes with diabetic retinopathy [J/OL]. Biosci Rep, 2017, 37(2): BSR20160589[2017-04-28]. http://europepmc.org/article/MED/28108673. DOI: 10.1042/BSR20160589.
38. Lu JM, Zhang ZZ, Ma X, et al. Repression of microRNA-21 inhibits retinal vascular endothelial cell growth and angiogenesis via PTEN dependent-PI3K/Akt/VEGF signaling pathway in diabetic retinopathy [J/OL]. Exp Eye Res, 2020, 190: 107886[2019-11-21]. https://linkinghub.elsevier.com/retrieve/pii/S0014-4835(18)30390-7. DOI: 10.1016/j.exer.2019.107886.
39. Yan B, Yao J, Liu JY, et al. lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA[J]. Circ Res, 2015, 116(7): 1143-1156. DOI: 10.1161/CIRCRESAHA.116.305510.
40. Shan K, Liu C, Liu BH, et al. Circular noncoding RNA HIPK3 mediates retinal vascular dysfunction in diabetes mellitus[J]. Circulation, 2017, 136(17): 1629-1642. DOI: 10.1161/CIRCULATIONAHA.117.029004.
41. Khan M, Walters LL, Li Q, et al. Characterization and pharmacologic targeting of EZH2, a fetal retinal protein and epigenetic regulator, in human retinoblastoma[J]. Lab Invest, 2015, 95(11): 1278-1290. DOI: 10.1038/labinvest.2015.104.
42. Huether R, Dong L, Chen X, et al. The landscape of somatic mutations in epigenetic regulators across 1, 000 paediatric cancer genomes [J/OL]. Nat Commun, 2014, 5: 3630[2014-04-08]. http://europepmc.org/article/MED/24710217. DOI: 10.1038/ncomms4630.
43. Choy KW, Pang CP, Yu CB, et al. Loss of heterozygosity and mutations are the major mechanisms of RB1 gene inactivation in Chinese with sporadic retinoblastoma[J]. Hum Mutat, 2002, 20(5): 408. DOI: 10.1002/humu.9077.
44. Ayari-Jeridi H, Moran K, Chebbi A, et al. Mutation spectrum of RB1 gene in unilateral retinoblastoma cases from Tunisia and correlations with clinical features [J/OL]. PLoS One, 2015, 10(1): 0116615[2015-01-20]. http://europepmc.org/article/MED/25602518. DOI: 10.1371/journal.pone.0116615.
45. Du J, Johnson LM, Jacobsen SE, et al. DNA methylation pathways and their crosstalk with histone methylation[J]. Nat Rev Mol Cell Biol, 2015, 16(9): 519-532. DOI: 10.1038/nrm4043.

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