Worldwide Type 2 Diabetic Retinopathy is one of the leading causes of blindness. It is the most frequently occurring complication of diabetes mellitus and remains a leading cause of vision loss in many countries. Although some potential functions of DNA methylation have been demonstrated already, many questions remain in terms of unveiling the role of 5caC; whether it serves either merely as an intermediate of DNA demethylation or as a stable epigenetic marker. 5-carboxylcytosine (5caC) is proved to be not merely serving as an intermediate of DNA demethylation, but also acts as a stable epigenetic marker. This review define how to control the gene expression and DNA Methylation in the CpGIsl and, The DNA Demethylation leads to convert the 5mc to 5hmc by the TeTprotein and again the 5hmc transfer to 5fc and further 5caC by the TeT enzyme in the BDNF gene. This review show the method to analyze the DNA Methylation at the 5-caC region for the BDNF gene and the fully mechanism which show the demethylation from 5hmc to 5fc and the pathway of DNA Demethylation from cytosine to 5-caC (5-Carboxylcytosine).

Keywords: Epigenetic Modification, DNA methylation, BDNF gene, 5-caC, CpGIs , Diabetic Retinopathy.

1. Stitt, A. W., Curtis, T. M., Chen, M., Medina, R. J., McKay, G. J., Jenkins, A., & Lois, N. (2016). The progress in understanding and treatment of diabetic retinopathy. Progress in Retinal and eye Research, 51, 156-186.
2. Barros, S. P., & Offenbacher, S. (2009). Epigenetics: connecting environment and genotype to phenotype and disease Journal of dental research, 88(5), 400-408.
3. Rose, N. R., & Klose, R. J. (2014). Understanding the relationship between DNA methylation and histone lysine methylation. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms, 1839(12), 1362-1372.
4. Lyko,F.(2017).TheDNA methyltransferase family: A versatile toolkit for epigenetic regulation. Nature Reviews Genetics, nrg-2017.
5. Gouri, A., &Dekaken, A. (2013). pathways in type 2 diabetes and its complications. ANNALS, 1(1), 1
6. Bhutani, N., Burns, D. M., &Blau, H. M. (2011). DNA demethylation dynamics. Cell, 146(6), 866-872.
7. Zhang, P. (2016). The regulation of Ten-eleven translocation proteins (methylcytosine modifiers) by methyl-CpG binding domain proteins (methylcytosine readers) (Doctoral dissertation, Technische Universität).
8. Kato M, Natarajan R. Diabetic nephropathy—emerging epigenetic mechanisms. Nat Rev Nephrol, 2014, 10: 517–530
9. Tewari S, Zhong Q, Santos JM, Kowluru RA. Mitochondria DNA replication and DNA methylation in the metabolic memory associated with continued progression of diabetic retinopathy. InvesOphthalmol Vis Sci, 2012, 53: 4881–4888
10. Williams KT, Garrow TA, Schalinske KL. Type I diabetes leads to tissue-specific DNA hypomethylation in male rats. J Nutr, 2008, 138: 2064–2069
11. Williams KT, Schalinske KL. Tissue-specific alterations of methyl group metabolism with DNA hypermethylation in the Zucker (type 2) diabetic fatty rat. Diabetes Metab Res Rev, 2012, 28: 123–131
12. Zhong Q, Kowluru RA. Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon. J Cell Biochem, 2010, 110: 1306–1313
13. Kadiyala CS, Zheng L, Du Y, Yohannes E, Kao HY, Miyagi M, Kern TS. Acetylation of retinal histones in diabetes increases inflammatory proteins: effects of minocycline and manipulation of histone acetyltransferase (HAT) and histone deacetylase (HDAC). J Biol Chem, 2012, 287: 25869–25880
14. Maghbooli Z, Hossein-Nezhad A, Larijani B, Amini M, Keshtkar A. Global DNA methylation as a possible biomarker for diabetic retinopathy. Diabetes Metab Res Rev, 2015, 31: 183–189
15. Maghbooli Z, Larijani B, Emamgholipour S, AminiM, Keshtkar A, Pasalar P. Aberrant DNA methylation patterns in diabetic nephropathy. J Diabetes MetabDisord, 2014, 13: 69
16. Frank RN. Diabetic retinopathy. N Engl J Med, 2004;350:48– 58.
17. May, S. E. (2014). An Investigation of Diabetes Mellitus in Postmortem Human Remains.
18. Lai CM, Dunlop SA, May LA, Gorbatov M, Brankov M, Shen WY, Binz N, Lai YK, Graham CE, Barry CJ, Constable IJ. Generation of transgenic mice with mild and severe retinal neovascularization. British journal of ophthalmology. 2005 Jul 1;89(7):911-6.
19. Yilmaz, T., & Yilmaz, A. (2016). Relationship between altered platelet morphological parameters and retinopathy in patients with type 2 diabetes mellitus. Journal of ophthalmology, 2016.
20. Curtis, T. M., Gardiner, T. A., & Stitt, A. W. (2009). Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?E3(ye, 27), 1496.
21. Robinson R, Barathi VA, Chaurasia SS, Wong TY, Kern TS. Update on animal models of diabetic retinopathy: from molecular approaches to mice and higher mammals. Disease models & mechanisms. 2012 Jul 1;5(4):444-56.
22. Nentwich, M. M., &Ulbig, M. W. (2015). Diabetic retinopathy-ocular complications of diabetes mellitus. World journal of diabetes, 6(3), 489
23. Barde YA, Edgar D, Thoenen H. Purification of a new neurotrophic factor from mammalian brain. EMBO J 1982;1:549–553.
24. Maisonpierre PC, et al. Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science 1990;247:1446–1451.
25. Hallbook F, Ibanez CF, Persson H. Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary. Neuron 1991;6:845–858.
26. Ip NY, et al. Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity. Proc Natl Acad Sci USA 1992;89:3060–3064.
27. Cattaneo, A., Cattane, N., Begni, V., Pariante, C. M., & Riva, M. A. (2016). The human BDNF gene: peripheral gene expression and protein levels as biomarkersfor psychiatric disorders. Translational psychiatry, 6(11), e958.
28. Nguyen, L., Lucke-Wold, B. P., Mookerjee, S. A., Cavendish, J. Z., Robson, M. J., Scandinaro, A. L., & Matsumoto, R. R. (2015). Role of sigma-1 receptors in neurodegenerative diseases. Journal of pharmacological sciences, 127(1), 17-29.
29. Mysona, B. A., Shanab, A. Y., Elshaer, S. L., & El-Remessy, A. B. (2014). Nerve growth factor in diabetic retinopathy: beyond neurons. Expert review of ophthalmology, 9(2), 99-107.
30. Menezes Zanoveli, J., de Morais, H., Caroline da Silva Dias, I., Karoline Schreiber, A., Pasquini de Souza, C., & Maria da Cunha, J. (2016). Depression associated with diabetes: from pathophysiology to treatment. Current diabetes reviews, 12(3), 165-178.
31. Rani, J., Mittal, I., Pramanik, A., Singh, N., Dube, N., Sharma, S., ... & Ramachandran, S. (2017). T2DiACoD: A Gene Atlas of Type 2 Diabetes Mellitus Associated Complex Disorders. Scientific reports, 7(1), 6892.
32. He, Y. F., Li, B. Z., Li, Z., Liu, P., Wang, Y., Tang, Q., ... & Sun, Y. (2011). Tet-mediated formation of5-carboxylcytosine and its excision by TDG in mammalian DNA. Science, 333(6047), 1303-1307.
33. Ito, S., Shen, L., Dai, Q., Wu, S. C., Collins, L. B., Swenberg, J. A., ... & Zhang, Y. (2011). Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science, 333(6047), 1300-1303.
34. Inoue, A., Shen, L., Dai, Q., He, C., & Zhang, Y. (2011). Generation and replication-dependent dilution of 5fC and 5caC during mouse preimplantation development. Cell research, 21(12), 1670.
35. Neri, F., Incarnato, D., Krepelova, A., Rapelli, S., Anselmi, F., Parlato, C., ... & Oliviero, S. (2015). Single-base resolution analysis of 5-formyl and 5-carboxyl cytosine reveals promoter DNA methylation dynamics. Cell reports, 10(5), 674-683.
36. Kurdyukov, S., & Bullock, M. (2016). DNA methylation analysis: choosing the right method. Biology, 5(1), 3.
37. Ola, M. S., Nawaz, M. I., El-Asrar, A. A., Abouammoh, M., &Alhomida, A. S. (2013). Reduced levels of brain derived neurotrophic factor (BDNF) in the serum of diabetic retinopathy patients and in the retina of diabetic rats. Cellular and molecular neurobiology, 33(3), 359-367.

Ambika Prasad Ahirwar

Email: This email address is being protected from spambots. You need JavaScript enabled to view it., Mob: 8085957699