Epigenetic Modifications Associated with the Pathogenesis of Type 2 Diabetes Mellitus

Author(s): Tareq Hossan*, Shoumik Kundu, Sayeda Sadia Alam, Sankari Nagarajan

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders

Volume 19 , Issue 6 , 2019

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Graphical Abstract:


Background and objective: Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder. Pancreatic β-cell dysfunction and insulin resistance are the most common and crucial events of T2DM. Increasing evidence suggests the association of epigenetic modifications with the pathogenesis of T2DM through the changes in important biological processes including pancreatic β- cell differentiation, development and maintenance of normal β-cell function. Insulin sensitivity by the peripheral glucose uptake tissues is also changed by the altered epigenetic mechanisms. In this review, we discussed the major epigenetic alterations and their effects on β-cell function, insulin secretion and insulin resistance in context of T2DM.

Methods: We investigated the presently available epigenetic modifications including DNA methylation, posttranslational histone modifications, ATP-dependent chromatin remodeling and non-coding RNAs related to the pathogenesis of T2DM. Published literatures on this topic were searched both on Google Scholar and Pubmed with related keywords and investigated for relevant information.

Results: The epigenetic modifications introduce changes in gene expression which are essential for appropriate β-cell development and functions, insulin secretion and sensitivity resulting in the pathogenesis of T2DM. Interestingly, T2DM could also be a prominent reason for the mentioned epigenetic alterations.

Conclusion: This review article emphasized on the epigenetic modifications associated with T2DM and discussed the consequences in deterioration of the disease condition.

Keywords: Type 2 diabetes mellitus, epigenetic, DNA methylation, histone modification, ATP-dependent chromatin remodeling, non-coding RNA, β cell, insulin resistance.

Roglic, G. WHO Global report on diabetes: A summary. Int. J. Non-Commun. Dis., 2016, 1(1), 3-8.
Forouhi, N.G.; Wareham, N.J. Epidemiology of diabetes. Medicine (Abingdon), 2014, 42(12), 698-702.
[http://dx.doi.org/10.1016/j.mpmed.2014.09.007] [PMID: 25568613]
Diagnosis and classification of diabetes mellitus. Diabetes Care, 2009, 32(1)(Suppl. 1), S62-S67.
[PMID: 19118289]
Wilcox, G. Insulin and insulin resistance. Clin. Biochem. Rev., 2005, 26(2), 19-39.
[PMID: 16278749]
Das, S.K.; Elbein, S.C. The Genetic Basis of Type 2 Diabetes. Cellscience, 2006, 2(4), 100-131.
[PMID: 16892160]
Steyn, N.P.; Mann, J.; Bennett, P.H.; Temple, N.; Zimmet, P.; Tuomilehto, J.; Lindström, J.; Louheranta, A. Diet, nutrition and the prevention of type 2 diabetes. Public Health Nutr., 2004, 7(1A), 147-165.
[http://dx.doi.org/10.1079/PHN2003586] [PMID: 14972058]
Moore, L.D.; Le, T.; Fan, G. DNA methylation and its basic function. Neuropsychopharmacology, 2013, 38(1), 23-38.
[http://dx.doi.org/10.1038/npp.2012.112] [PMID: 22781841]
Handy, D.E.; Castro, R.; Loscalzo, J. Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation, 2011, 123(19), 2145-2156.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.110.956839] [PMID: 21576679]
Bird, A.; Taggart, M.; Frommer, M.; Miller, O.J.; Macleod, D. A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell, 1985, 40(1), 91-99.
[http://dx.doi.org/10.1016/0092-8674(85)90312-5] [PMID: 2981636]
Deaton, A.M.; Bird, A. CpG islands and the regulation of transcription. Genes Dev., 2011, 25(10), 1010-1022.
[http://dx.doi.org/10.1101/gad.2037511] [PMID: 21576262]
Costello, J.F.; Plass, C. Methylation matters. J. Med. Genet., 2001, 38(5), 285-303.
[http://dx.doi.org/10.1136/jmg.38.5.285] [PMID: 11333864]
Adcock, I.M.; Ford, P.; Ito, K.; Barnes, P.J. Epigenetics and airways disease. Respir. Res., 2006, 7(1), 21.
[http://dx.doi.org/10.1186/1465-9921-7-21] [PMID: 16460559]
Wong, C.C.Y.; Mill, J.; Fernandes, C. Drugs and addiction: An introduction to epigenetics. Addiction, 2011, 106(3), 480-489.
[http://dx.doi.org/10.1111/j.1360-0443.2010.03321.x] [PMID: 21205049]
Bannister, A.J.; Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res., 2011, 21(3), 381-395.
[http://dx.doi.org/10.1038/cr.2011.22] [PMID: 21321607]
Sadakierska-Chudy, A.; Filip, M. A comprehensive view of the epigenetic landscape. Part II: Histone post-translational modification, nucleosome level, and chromatin regulation by ncRNAs. Neurotox. Res., 2015, 27(2), 172-197.
[http://dx.doi.org/10.1007/s12640-014-9508-6] [PMID: 25516120]
Zhou, V.W.; Goren, A.; Bernstein, B.E. Charting histone modifications and the functional organization of mammalian genomes. Nat. Rev. Genet., 2011, 12(1), 7-18.
[http://dx.doi.org/10.1038/nrg2905] [PMID: 21116306]
Zhang, T.; Cooper, S.; Brockdorff, N. The interplay of histone modifications - writers that read. EMBO Rep., 2015, 16(11), 1467-1481.
[http://dx.doi.org/10.15252/embr.201540945] [PMID: 26474904]
Geisler, S.; Coller, J. RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat. Rev. Mol. Cell Biol., 2013, 14(11), 699-712.
[http://dx.doi.org/10.1038/nrm3679] [PMID: 24105322]
Pal, S.; Tyler, J.K. Epigenetics and aging. Sci. Adv., 2016, 2(7)e1600584
[http://dx.doi.org/10.1126/sciadv.1600584] [PMID: 27482540]
Qureshi, I.A.; Mehler, M.F. Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease. Nat. Rev. Neurosci., 2012, 13(8), 528-541.
[http://dx.doi.org/10.1038/nrn3234] [PMID: 22814587]
Lujambio, A.; Calin, G.A.; Villanueva, A.; Ropero, S.; Sánchez-Céspedes, M.; Blanco, D.; Montuenga, L.M.; Rossi, S.; Nicoloso, M.S.; Faller, W.J.; Gallagher, W.M.; Eccles, S.A.; Croce, C.M.; Esteller, M. A microRNA DNA methylation signature for human cancer metastasis. Proc. Natl. Acad. Sci. USA, 2008, 105(36), 13556-13561.
[http://dx.doi.org/10.1073/pnas.0803055105] [PMID: 18768788]
Barter, M.J.; Bui, C.; Young, D.A. Epigenetic mechanisms in cartilage and osteoarthritis: DNA methylation, histone modifications and microRNAs. Osteoarthritis Cartilage, 2012, 20(5), 339-349.
[http://dx.doi.org/10.1016/j.joca.2011.12.012] [PMID: 22281264]
Portela, A.; Esteller, M. Epigenetic modifications and human disease. Nat. Biotechnol., 2010, 28(10), 1057-1068.
[http://dx.doi.org/10.1038/nbt.1685] [PMID: 20944598]
Goto, K.; Numata, M.; Komura, J.I.; Ono, T.; Bestor, T.H.; Kondo, H. Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. Differentiation, 1994, 56(1-2), 39-44.
[http://dx.doi.org/10.1046/j.1432-0436.1994.56120039.x] [PMID: 8026645]
Feng, J.; Chang, H.; Li, E.; Fan, G. Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. J. Neurosci. Res., 2005, 79(6), 734-746.
[http://dx.doi.org/10.1002/jnr.20404] [PMID: 15672446]
Dayeh, T.; Ling, C. Does epigenetic dysregulation of pancreatic islets contribute to impaired insulin secretion and type 2 diabetes? Biochem. Cell Biol., 2015, 93(5), 511-521.
[http://dx.doi.org/10.1139/bcb-2015-0057] [PMID: 26369706]
Volkmar, M.; Dedeurwaerder, S.; Cunha, D.A.; Ndlovu, M.N.; Defrance, M.; Deplus, R.; Calonne, E.; Volkmar, U.; Igoillo-Esteve, M.; Naamane, N.; Del Guerra, S.; Masini, M.; Bugliani, M.; Marchetti, P.; Cnop, M.; Eizirik, D.L.; Fuks, F. DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J., 2012, 31(6), 1405-1426.
[http://dx.doi.org/10.1038/emboj.2011.503] [PMID: 22293752]
Dayeh, T.; Volkov, P.; Salö, S.; Hall, E.; Nilsson, E.; Olsson, A.H.; Kirkpatrick, C.L.; Wollheim, C.B.; Eliasson, L.; Rönn, T.; Bacos, K.; Ling, C. Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet., 2014, 10(3)e1004160
[http://dx.doi.org/10.1371/journal.pgen.1004160] [PMID: 24603685]
Volkov, P.; Bacos, K.; Ofori, J.K.; Esguerra, J.L.S.; Eliasson, L.; Rönn, T.; Ling, C. Whole-Genome Bisulfite Sequencing of Human Pancreatic Islets Reveals Novel Differentially Methylated Regions in Type 2 Diabetes Pathogenesis. Diabetes, 2017, 66(4), 1074-1085.
[http://dx.doi.org/10.2337/db16-0996] [PMID: 28052964]
Yang, B.T.; Dayeh, T.A.; Kirkpatrick, C.L.; Taneera, J.; Kumar, R.; Groop, L.; Wollheim, C.B.; Nitert, M.D.; Ling, C. Insulin promoter DNA methylation correlates negatively with insulin gene expression and positively with HbA(1c) levels in human pancreatic islets. Diabetologia, 2011, 54(2), 360-367.
[http://dx.doi.org/10.1007/s00125-010-1967-6] [PMID: 21104225]
Yang, B.T.; Dayeh, T.A.; Volkov, P.A.; Kirkpatrick, C.L.; Malmgren, S.; Jing, X.; Renström, E.; Wollheim, C.B.; Nitert, M.D.; Ling, C. Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes. Mol. Endocrinol., 2012, 26(7), 1203-1212.
[http://dx.doi.org/10.1210/me.2012-1004] [PMID: 22570331]
Jonsson, J.; Carlsson, L.; Edlund, T.; Edlund, H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature, 1994, 371(6498), 606-609.
[http://dx.doi.org/10.1038/371606a0] [PMID: 7935793]
Kaneto, H.; Miyatsuka, T.; Kawamori, D.; Yamamoto, K.; Kato, K.; Shiraiwa, T.; Katakami, N.; Yamasaki, Y.; Matsuhisa, M.; Matsuoka, T.A. PDX-1 and MafA play a crucial role in pancreatic β-cell differentiation and maintenance of mature β-cell function. Endocr. J., 2008, 55(2), 235-252.
[http://dx.doi.org/10.1507/endocrj.K07E-041] [PMID: 17938503]
Ling, C.; Del Guerra, S.; Lupi, R.; Rönn, T.; Granhall, C.; Luthman, H.; Masiello, P.; Marchetti, P.; Groop, L.; Del Prato, S. Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia, 2008, 51(4), 615-622.
[http://dx.doi.org/10.1007/s00125-007-0916-5] [PMID: 18270681]
Hall, E.; Dayeh, T.; Kirkpatrick, C.L.; Wollheim, C.B. Dek-ker Nitert, M.; Ling, C. DNA Methylation of the Glucagon-like Peptide 1 Receptor (GLP1R) in Human Pancreatic Islets. BMC Med. Genet., 2013, 14, 2-7.
Davegårdh, C.; García-Calzón, S.; Bacos, K.; Ling, C. DNA methylation in the pathogenesis of type 2 diabetes in humans. Mol. Metab., 2018, 14, 12-25.
[http://dx.doi.org/10.1016/j.molmet.2018.01.022] [PMID: 29496428]
Rönn, T.; Ling, C. DNA methylation as a diagnostic and therapeutic target in the battle against Type 2 diabetes. Epigenomics, 2015, 7(3), 451-460.
[http://dx.doi.org/10.2217/epi.15.7] [PMID: 26077431]
Nilsson, E.; Jansson, P.A.; Perfilyev, A.; Volkov, P.; Pedersen, M.; Svensson, M.K.; Poulsen, P.; Ribel-Madsen, R.; Pedersen, N.L.; Almgren, P.; Fadista, J.; Rönn, T.; Klarlund Pedersen, B.; Scheele, C.; Vaag, A.; Ling, C. Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes. Diabetes, 2014, 63(9), 2962-2976.
[http://dx.doi.org/10.2337/db13-1459] [PMID: 24812430]
Ribel-Madsen, R.; Fraga, M.F.; Jacobsen, S.; Bork-Jensen, J.; Lara, E.; Calvanese, V.; Fernandez, A.F.; Friedrichsen, M.; Vind, B.F.; Højlund, K.; Beck-Nielsen, H.; Esteller, M.; Vaag, A.; Poulsen, P. Genome-wide analysis of DNA methylation differences in muscle and fat from monozygotic twins discordant for type 2 diabetes. PLoS One, 2012, 7(12)e51302
[http://dx.doi.org/10.1371/journal.pone.0051302] [PMID: 23251491]
Barnard, R.J.; Youngren, J.F. Regulation of glucose transport in skeletal muscle. FASEB J., 1992, 6(14), 3238-3244.
[http://dx.doi.org/10.1096/fasebj.6.14.1426762] [PMID: 1426762]
Rönn, T.; Volkov, P.; Davegårdh, C.; Dayeh, T.; Hall, E.; Olsson, A.H.; Nilsson, E.; Tornberg, A.; Dekker Nitert, M.; Eriksson, K-F.; Jones, H.A.; Groop, L.; Ling, C. A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue. PLoS Genet., 2013, 9(6)e1003572
[http://dx.doi.org/10.1371/journal.pgen.1003572] [PMID: 23825961]
Barrès, R.; Osler, M.E.; Yan, J.; Rune, A.; Fritz, T.; Caidahl, K.; Krook, A.; Zierath, J.R. Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density. Cell Metab., 2009, 10(3), 189-198.
[http://dx.doi.org/10.1016/j.cmet.2009.07.011] [PMID: 19723495]
Ling, C.; Poulsen, P.; Simonsson, S.; Rönn, T.; Holmkvist, J.; Almgren, P.; Hagert, P.; Nilsson, E.; Mabey, A.G.; Nilsson, P.; Vaag, A.; Groop, L. Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. J. Clin. Invest., 2007, 117(11), 3427-3435.
[http://dx.doi.org/10.1172/JCI30938] [PMID: 17948130]
Kulkarni, S.S.; Salehzadeh, F.; Fritz, T.; Zierath, J.R.; Krook, A.; Osler, M.E. Mitochondrial regulators of fatty acid metabolism reflect metabolic dysfunction in type 2 diabetes mellitus. Metabolism, 2012, 61(2), 175-185.
[http://dx.doi.org/10.1016/j.metabol.2011.06.014] [PMID: 21816445]
Röhling, M.; Herder, C.; Stemper, T.; Müssig, K. Influence of Acute and Chronic Exercise on Glucose Uptake. J. Diabetes Res., 2016.20162868652
[http://dx.doi.org/10.1155/2016/2868652] [PMID: 27069930]
Barrès, R.; Yan, J.; Egan, B.; Treebak, J.T.; Rasmussen, M.; Fritz, T.; Caidahl, K.; Krook, A.; O’Gorman, D.J.; Zierath, J.R. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab., 2012, 15(3), 405-411.
[http://dx.doi.org/10.1016/j.cmet.2012.01.001] [PMID: 22405075]
Rönn, T.; Ling, C. Effect of exercise on DNA methylation and metabolism in human adipose tissue and skeletal muscle. Epigenomics, 2013, 5(6), 603-605.
[http://dx.doi.org/10.2217/epi.13.61] [PMID: 24283873]
Gillberg, L.; Perfilyev, A.; Brøns, C.; Thomasen, M.; Grunnet, L.G.; Volkov, P.; Rosqvist, F.; Iggman, D.; Dahlman, I.; Risérus, U.; Rönn, T.; Nilsson, E.; Vaag, A.; Ling, C. Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding. Diabetologia, 2016, 59(4), 799-812.
[http://dx.doi.org/10.1007/s00125-015-3852-9] [PMID: 26750116]
Ferrannini, E.; Barrett, E.J.; Bevilacqua, S.; DeFronzo, R.A. Effect of fatty acids on glucose production and utilization in man. J. Clin. Invest., 1983, 72(5), 1737-1747.
[http://dx.doi.org/10.1172/JCI111133] [PMID: 6138367]
Krssak, M.; Falk Petersen, K.; Dresner, A.; DiPietro, L.; Vogel, S.M.; Rothman, D.L.; Roden, M.; Shulman, G.I. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia, 1999, 42(1), 113-116.
[http://dx.doi.org/10.1007/s001250051123] [PMID: 10027589]
Johnson, A.B.; Argyraki, M.; Thow, J.C.; Cooper, B.G.; Fulcher, G.; Taylor, R. Effect of increased free fatty acid supply on glucose metabolism and skeletal muscle glycogen synthase activity in normal man. Clin. Sci. (Lond.), 1992, 82(2), 219-226.
[http://dx.doi.org/10.1042/cs0820219] [PMID: 1311661]
Jacobsen, S.C.; Brøns, C.; Bork-Jensen, J.; Ribel-Madsen, R.; Yang, B.; Lara, E.; Hall, E.; Calvanese, V.; Nilsson, E.; Jørgensen, S.W.; Mandrup, S.; Ling, C.; Fernandez, A.F.; Fraga, M.F.; Poulsen, P.; Vaag, A. Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men. Diabetologia, 2012, 55(12), 3341-3349.
[http://dx.doi.org/10.1007/s00125-012-2717-8] [PMID: 22961225]
Zhao, J.; Goldberg, J.; Bremner, J.D.; Vaccarino, V. Global DNA methylation is associated with insulin resistance: a monozygotic twin study. Diabetes, 2012, 61(2), 542-546.
[http://dx.doi.org/10.2337/db11-1048] [PMID: 22210312]
Gu, H.F.; Gu, T.; Hilding, A.; Zhu, Y.; Kärvestedt, L.; Östenson, C-G.; Lai, M.; Kutsukake, M.; Frystyk, J.; Tamura, K.; Brismar, K. Evaluation of IGFBP-7 DNA methylation changes and serum protein variation in Swedish subjects with and without type 2 diabetes. Clin. Epigenetics, 2013, 5(1), 20.
[http://dx.doi.org/10.1186/1868-7083-5-20] [PMID: 24180466]
Simar, D.; Versteyhe, S.; Donkin, I.; Liu, J.; Hesson, L.; Nylander, V.; Fossum, A.; Barrès, R. DNA methylation is altered in B and NK lymphocytes in obese and type 2 diabetic human. Metabolism, 2014, 63(9), 1188-1197.
[http://dx.doi.org/10.1016/j.metabol.2014.05.014] [PMID: 24996265]
Jiang, M.H.; Fei, J.; Lan, M.S.; Lu, Z.P.; Liu, M.; Fan, W.W.; Gao, X.; Lu, D.R. Hypermethylation of hepatic Gck promoter in ageing rats contributes to diabetogenic potential. Diabetologia, 2008, 51(8), 1525-1533.
[http://dx.doi.org/10.1007/s00125-008-1034-8] [PMID: 18496667]
Jiang, M.; Zhang, Y.; Liu, M.; Lan, M.S.; Fei, J.; Fan, W.; Gao, X.; Lu, D. Hypermethylation of hepatic glucokinase and L-type pyruvate kinase promoters in high-fat diet-induced obese rats. Endocrinology, 2011, 152(4), 1284-1289.
[http://dx.doi.org/10.1210/en.2010-1162] [PMID: 21239437]
Gemma, C.; Sookoian, S.; Dieuzeide, G.; García, S.I.; Gianotti, T.F.; González, C.D.; Pirola, C.J. Methylation of TFAM gene promoter in peripheral white blood cells is associated with insulin resistance in adolescents. Mol. Genet. Metab., 2010, 100(1), 83-87.
[http://dx.doi.org/10.1016/j.ymgme.2010.02.004] [PMID: 20202876]
Bhandare, R.; Schug, J.; Le Lay, J.; Fox, A.; Smirnova, O.; Liu, C.; Naji, A.; Kaestner, K.H. Genome-wide analysis of histone modifications in human pancreatic islets. Genome Res., 2010, 20(4), 428-433.
[http://dx.doi.org/10.1101/gr.102038.109] [PMID: 20181961]
Chakrabarti, S.K.; Francis, J.; Ziesmann, S.M.; Garmey, J.C.; Mirmira, R.G. Covalent histone modifications underlie the developmental regulation of insulin gene transcription in pancreatic β cells. J. Biol. Chem., 2003, 278(26), 23617-23623.
[http://dx.doi.org/10.1074/jbc.M303423200] [PMID: 12711597]
Francis, J.; Chakrabarti, S.K.; Garmey, J.C.; Mirmira, R.G. Pdx-1 links histone H3-Lys-4 methylation to RNA polymerase II elongation during activation of insulin transcription. J. Biol. Chem., 2005, 280(43), 36244-36253.
[http://dx.doi.org/10.1074/jbc.M505741200] [PMID: 16141209]
Jufvas, Å.; Sjödin, S.; Lundqvist, K.; Amin, R.; Vener, A.V.; Strålfors, P. Global Differences in Specific Histone H3 Methylation Are Associated with Overweight and Type 2 Diabetes. Clin. Epigenetics, 2013, 5(1), 1-6.
[http://dx.doi.org/10.1186/1868-7083-5-15] [PMID: 23286427]
Tu, P.; Li, X.; Ma, B.; Duan, H.; Zhang, Y.; Wu, R.; Ni, Z.; Jiang, P.; Wang, H.; Li, M.; Zhu, J.; Li, M. Liver histone H3 methylation and acetylation may associate with type 2 diabetes development. J. Physiol. Biochem., 2015, 71(1), 89-98.
[http://dx.doi.org/10.1007/s13105-015-0385-0] [PMID: 25666660]
Uldry, M.; Thorens, B. The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch., 2004, 447(5), 480-489.
[http://dx.doi.org/10.1007/s00424-003-1085-0] [PMID: 12750891]
Lau, O.D.; Kundu, T.K.; Soccio, R.E.; Ait-Si-Ali, S.; Khalil, E.M.; Vassilev, A.; Wolffe, A.P.; Nakatani, Y.; Roeder, R.G.; Cole, P.A. HATs off: selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF. Mol. Cell, 2000, 5(3), 589-595.
[http://dx.doi.org/10.1016/S1097-2765(00)80452-9] [PMID: 10882143]
Qiu, Y.; Sharma, A.; Stein, R. p300 mediates transcriptional stimulation by the basic helix-loop-helix activators of the insulin gene. Mol. Cell. Biol., 1998, 18(5), 2957-2964.
[http://dx.doi.org/10.1128/MCB.18.5.2957] [PMID: 9566915]
Barnes, P.J.; Adcock, I.M.; Ito, K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur. Respir. J., 2005, 25(3), 552-563.
[http://dx.doi.org/10.1183/09031936.05.00117504] [PMID: 15738302]
Park, J.H.; Stoffers, D.A.; Nicholls, R.D.; Simmons, R.A. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J. Clin. Invest., 2008, 118(6), 2316-2324.
[http://dx.doi.org/10.1172/JCI33655] [PMID: 18464933]
Christensen, D.P.; Dahllöf, M.; Lundh, M.; Rasmussen, D.N.; Nielsen, M.D.; Billestrup, N.; Grunnet, L.G.; Mandrup-Poulsen, T. Histone deacetylase (HDAC) inhibition as a novel treatment for diabetes mellitus. Mol. Med., 2011, 17(5-6), 378-390.
[http://dx.doi.org/10.2119/molmed.2011.00021] [PMID: 21274504]
Raychaudhuri, N.; Raychaudhuri, S.; Thamotharan, M.; Devaskar, S.U. Histone code modifications repress glucose transporter 4 expression in the intrauterine growth-restricted offspring. J. Biol. Chem., 2008, 283(20), 13611-13626.
[http://dx.doi.org/10.1074/jbc.M800128200] [PMID: 18326493]
Kim, H-J.; Bae, S-C. Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am. J. Transl. Res., 2011, 3(2), 166-179.
[PMID: 21416059]
Wang, X.; Wei, X.; Pang, Q.; Yi, F. Histone Deacetylases and Their Inhibitors: Molecular Mechanisms and Therapeutic Im-plications in Diabetes Mellitus. Acta Pharm. Sin. B, 2012, 2(4), 387-395.
Sharma, S.; Taliyan, R. Histone deacetylase inhibitors: Future therapeutics for insulin resistance and type 2 diabetes Pharmacol. Res, 2016, 113(Pt A), 320-326
[http://dx.doi.org/10.1016/j.phrs.2016.09.009] [PMID: 27620069]
Wang, R-R.; Pan, R.; Zhang, W.; Fu, J.; Lin, J.D.; Meng, Z-X. The SWI/SNF chromatin-remodeling factors BAF60a, b, and c in nutrient signaling and metabolic control. Protein Cell, 2018, 9(2), 207-215.
[http://dx.doi.org/10.1007/s13238-017-0442-2] [PMID: 28688083]
Lee, Y.S.; Sohn, D.H.; Han, D.; Lee, H-W.; Seong, R.H.; Kim, J.B. Chromatin remodeling complex interacts with ADD1/SREBP1c to mediate insulin-dependent regulation of gene expression. Mol. Cell. Biol., 2007, 27(2), 438-452.
[http://dx.doi.org/10.1128/MCB.00490-06] [PMID: 17074803]
Masliah-Planchon, J.; Bièche, I.; Guinebretière, J-M.; Bourdeaut, F.; Delattre, O. SWI/SNF chromatin remodeling and human malignancies. Annu. Rev. Pathol., 2015, 10, 145-171.
[http://dx.doi.org/10.1146/annurev-pathol-012414-040445] [PMID: 25387058]
Denslow, S.A.; Wade, P.A. The human Mi-2/NuRD complex and gene regulation. Oncogene, 2007, 26(37), 5433-5438.
[http://dx.doi.org/10.1038/sj.onc.1210611] [PMID: 17694084]
Spaeth, J.M.; Walker, E.M.; Stein, R. Impact of Pdx1-associated chromatin modifiers on islet β-cells. Diabetes Obes. Metab., 2016, 18(1)(Suppl. 1), 123-127.
[http://dx.doi.org/10.1111/dom.12730] [PMID: 27615141]
Kadam, S.; Emerson, B.M. Transcriptional specificity of human SWI/SNF BRG1 and BRM chromatin remodeling complexes. Mol. Cell, 2003, 11(2), 377-389.
[http://dx.doi.org/10.1016/S1097-2765(03)00034-0] [PMID: 12620226]
McKenna, B.; Guo, M.; Reynolds, A.; Hara, M.; Stein, R. Dynamic recruitment of functionally distinct Swi/Snf chromatin remodeling complexes modulates Pdx1 activity in islet β cells. Cell Rep., 2015, 10(12), 2032-2042.
[http://dx.doi.org/10.1016/j.celrep.2015.02.054] [PMID: 25801033]
Gao, T.; McKenna, B.; Li, C.; Reichert, M.; Nguyen, J.; Singh, T.; Yang, C.; Pannikar, A.; Doliba, N.; Zhang, T.; Stoffers, D.A.; Edlund, H.; Matschinsky, F.; Stein, R.; Stanger, B.Z. Pdx1 maintains β cell identity and function by repressing an α cell program. Cell Metab., 2014, 19(2), 259-271.
[http://dx.doi.org/10.1016/j.cmet.2013.12.002] [PMID: 24506867]
Raut, S.K.; Khullar, M. The Big Entity of New RNA World: Long Non-Coding RNAs in Microvascular Complications of Diabetes. Front. Endocrinol. (Lausanne), 2018, 9, 300.
[http://dx.doi.org/10.3389/fendo.2018.00300] [PMID: 29915562]
Akerman, I.; Tu, Z.; Beucher, A.; Rolando, D.M.Y.; Sauty-Colace, C.; Benazra, M.; Nakic, N.; Yang, J.; Wang, H.; Pasquali, L.; Moran, I.; Garcia-Hurtado, J.; Castro, N.; Gonzalez-Franco, R.; Stewart, A.F.; Bonner, C.; Piemonti, L.; Berney, T.; Groop, L.; Kerr-Conte, J.; Pattou, F.; Argmann, C.; Schadt, E.; Ravassard, P.; Ferrer, J. Human Pancreatic β Cell lncRNAs Control Cell-Specific Regulatory Networks. Cell Metab., 2017, 25(2), 400-411.
[http://dx.doi.org/10.1016/j.cmet.2016.11.016] [PMID: 28041957]
Cebola, I.; Pasquali, L. Non-coding genome functions in diabetes. J. Mol. Endocrinol., 2016, 56(1), R1-R20.
[http://dx.doi.org/10.1530/JME-15-0197] [PMID: 26438568]
Morán, I.; Akerman, I.; van de Bunt, M.; Xie, R.; Benazra, M.; Nammo, T.; Arnes, L.; Nakić, N.; García-Hurtado, J.; Rodríguez-Seguí, S.; Pasquali, L.; Sauty-Colace, C.; Beucher, A.; Scharfmann, R.; van Arensbergen, J.; Johnson, P.R.; Berry, A.; Lee, C.; Harkins, T.; Gmyr, V.; Pattou, F.; Kerr-Conte, J.; Piemonti, L.; Berney, T.; Hanley, N.; Gloyn, A.L.; Sussel, L.; Langman, L.; Brayman, K.L.; Sander, M.; McCarthy, M.I.; Ravassard, P.; Ferrer, J. Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab., 2012, 16(4), 435-448.
[http://dx.doi.org/10.1016/j.cmet.2012.08.010] [PMID: 23040067]
Motterle, A.; Gattesco, S.; Peyot, M-L.; Esguerra, J.L.S.; Gomez-Ruiz, A.; Laybutt, D.R.; Gilon, P.; Burdet, F.; Ibberson, M.; Eliasson, L.; Prentki, M.; Regazzi, R. Identification of islet-enriched long non-coding RNAs contributing to β-cell failure in type 2 diabetes. Mol. Metab., 2017, 6(11), 1407-1418.
[http://dx.doi.org/10.1016/j.molmet.2017.08.005] [PMID: 29107288]
Forbes, J.M.; Cooper, M.E. Mechanisms of diabetic complications. Physiol. Rev., 2013, 93(1), 137-188.
[http://dx.doi.org/10.1152/physrev.00045.2011] [PMID: 23303908]
Leti, F.; DiStefano, J.K.; Leti, F.; DiStefano, J.K. Long Noncoding RNAs as Diagnostic and Therapeutic Targets in Type 2 Diabetes and Related Complications. Genes (Basel), 2017, 8(8), 1-19.
[PMID: 28829354]
Reddy, M.A.; Zhang, E.; Natarajan, R. Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia, 2015, 58(3), 443-455.
[http://dx.doi.org/10.1007/s00125-014-3462-y] [PMID: 25481708]
Macfarlane, L-A.; Murphy, P.R. MicroRNA: Biogenesis, Function and Role in Cancer. Curr. Genomics, 2010, 11(7), 537-561.
[http://dx.doi.org/10.2174/138920210793175895] [PMID: 21532838]
Hausser, J.; Zavolan, M. Identification and consequences of miRNA-target interactions--beyond repression of gene expression. Nat. Rev. Genet., 2014, 15(9), 599-612.
[http://dx.doi.org/10.1038/nrg3765] [PMID: 25022902]
Villeneuve, L.M.; Natarajan, R. The role of epigenetics in the pathology of diabetic complications. Am. J. Physiol. Renal Physiol., 2010, 299(1), F14-F25.
[http://dx.doi.org/10.1152/ajprenal.00200.2010] [PMID: 20462972]
Beltrami, C.; Angelini, T.G.; Emanueli, C. Noncoding RNAs in diabetes vascular complications. J. Mol. Cell. Cardiol, 2015, 89(Pt A), 42-50.
[http://dx.doi.org/10.1016/j.yjmcc.2014.12.014] [PMID: 25536178]
van de Bunt, M.; Gaulton, K.J.; Parts, L.; Moran, I.; Johnson, P.R.; Lindgren, C.M.; Ferrer, J.; Gloyn, A.L.; McCarthy, M.I. The miRNA profile of human pancreatic islets and beta-cells and relationship to type 2 diabetes pathogenesis. PLoS One, 2013, 8(1)e55272
[http://dx.doi.org/10.1371/journal.pone.0055272] [PMID: 23372846]
Lynn, F.C.; Skewes-Cox, P.; Kosaka, Y.; McManus, M.T.; Harfe, B.D.; German, M.S. MicroRNA expression is required for pancreatic islet cell genesis in the mouse. Diabetes, 2007, 56(12), 2938-2945.
[http://dx.doi.org/10.2337/db07-0175] [PMID: 17804764]
LaPierre, M.P.; Stoffel, M. MicroRNAs as stress regulators in pancreatic beta cells and diabetes. Mol. Metab., 2017, 6(9), 1010-1023.
[http://dx.doi.org/10.1016/j.molmet.2017.06.020] [PMID: 28951825]
Berry, C.; Lal, M.; Binukumar, B.K. Crosstalk Between the Unfolded Protein Response, MicroRNAs, and Insulin Signal-ing Pathways: In Search of Biomarkers for the Diagnosis and Treatment of Type 2 Diabetes. Front. Endocrinol., 2018, 9, 1-15.
El Ouaamari, A.; Baroukh, N.; Martens, G.A.; Lebrun, P.; Pipeleers, D.; van Obberghen, E. miR-375 targets 3′-phosphoinositide-dependent protein kinase-1 and regulates glucose-induced biological responses in pancreatic beta-cells. Diabetes, 2008, 57(10), 2708-2717.
[http://dx.doi.org/10.2337/db07-1614] [PMID: 18591395]
Poy, M.N.; Eliasson, L.; Krutzfeldt, J.; Kuwajima, S.; Ma, X.; Macdonald, P.E.; Pfeffer, S.; Tuschl, T.; Rajewsky, N.; Rorsman, P.; Stoffel, M. A pancreatic islet-specific microRNA regulates insulin secretion. Nature, 2004, 432(7014), 226-230.
[http://dx.doi.org/10.1038/nature03076] [PMID: 15538371]
Latreille, M.; Hausser, J.; Stützer, I.; Zhang, Q.; Hastoy, B.; Gargani, S.; Kerr-Conte, J.; Pattou, F.; Zavolan, M.; Esguerra, J.L.S.; Eliasson, L.; Rülicke, T.; Rorsman, P.; Stoffel, M. MicroRNA-7a regulates pancreatic β cell function. J. Clin. Invest., 2014, 124(6), 2722-2735.
[http://dx.doi.org/10.1172/JCI73066] [PMID: 24789908]
Ling, H-Y.; Ou, H-S.; Feng, S-D.; Zhang, X-Y.; Tuo, Q-H.; Chen, L-X.; Zhu, B-Y.; Gao, Z-P.; Tang, C-K.; Yin, W-D.; Zhang, L.; Liao, D.F. Changes in microRNA (miR) profile and effects of miR-320 in insulin-resistant 3T3-L1 adipocytes. Clin. Exp. Pharmacol. Physiol., 2009, 36(9), e32-e39.
[http://dx.doi.org/10.1111/j.1440-1681.2009.05207.x] [PMID: 19473196]
Karbiener, M.; Fischer, C.; Nowitsch, S.; Opriessnig, P.; Papak, C.; Ailhaud, G.; Dani, C.; Amri, E-Z.; Scheideler, M. microRNA miR-27b impairs human adipocyte differentiation and targets PPARgamma. Biochem. Biophys. Res. Commun., 2009, 390(2), 247-251.
[http://dx.doi.org/10.1016/j.bbrc.2009.09.098] [PMID: 19800867]
Sebastiani, G.; Po, A.; Miele, E.; Ventriglia, G.; Ceccarelli, E.; Bugliani, M.; Marselli, L.; Marchetti, P.; Gulino, A.; Ferretti, E.; Dotta, F. MicroRNA-124a is hyperexpressed in type 2 diabetic human pancreatic islets and negatively regulates insulin secretion. Acta Diabetol., 2015, 52(3), 523-530.
[http://dx.doi.org/10.1007/s00592-014-0675-y] [PMID: 25408296]
Pheiffer, C.; Erasmus, R.T.; Kengne, A.P.; Matsha, T.E. Differential DNA methylation of microRNAs within promoters, intergenic and intragenic regions of type 2 diabetic, pre-diabetic and non-diabetic individuals. Clin. Biochem., 2016, 49(6), 433-438.
[http://dx.doi.org/10.1016/j.clinbiochem.2015.11.021] [PMID: 26656639]
Chakraborty, C.; Doss, C.G.P.; Bandyopadhyay, S.; Agoramoorthy, G. Influence of miRNA in insulin signaling pathway and insulin resistance: micro-molecules with a major role in type-2 diabetes. Wiley Interdiscip. Rev. RNA, 2014, 5(5), 697-712.
[http://dx.doi.org/10.1002/wrna.1240] [PMID: 24944010]
Visel, A.; Rubin, E.M.; Pennacchio, L.A. Genomic views of distant-acting enhancers. Nature, 2009, 461(7261), 199-205.
[http://dx.doi.org/10.1038/nature08451] [PMID: 19741700]
Bejerano, G.; Lowe, C.B.; Ahituv, N.; King, B.; Siepel, A.; Salama, S.R.; Rubin, E.M.; Kent, W.J.; Haussler, D. A distal enhancer and an ultraconserved exon are derived from a novel retroposon. Nature, 2006, 441(7089), 87-90.
[http://dx.doi.org/10.1038/nature04696] [PMID: 16625209]
Heintzman, N.D.; Hon, G.C.; Hawkins, R.D.; Kheradpour, P.; Stark, A.; Harp, L.F.; Ye, Z.; Lee, L.K.; Stuart, R.K.; Ching, C.W.; Ching, K.A.; Antosiewicz-Bourget, J.E.; Liu, H.; Zhang, X.; Green, R.D.; Lobanenkov, V.V.; Stewart, R.; Thomson, J.A.; Crawford, G.E.; Kellis, M.; Ren, B. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature, 2009, 459(7243), 108-112.
[http://dx.doi.org/10.1038/nature07829] [PMID: 19295514]
Danko, C.G.; Hah, N.; Luo, X.; Martins, A.L.; Core, L.; Lis, J.T.; Siepel, A.; Kraus, W.L. Signaling pathways differentially affect RNA polymerase II initiation, pausing, and elongation rate in cells. Mol. Cell, 2013, 50(2), 212-222.
[http://dx.doi.org/10.1016/j.molcel.2013.02.015] [PMID: 23523369]
Hah, N.; Murakami, S.; Nagari, A.; Danko, C.G.; Kraus, W.L. Enhancer transcripts mark active estrogen receptor binding sites. Genome Res., 2013, 23(8), 1210-1223.
[http://dx.doi.org/10.1101/gr.152306.112] [PMID: 23636943]
Arnes, L.; Sussel, L. Epigenetic modifications and long noncoding RNAs influence pancreas development and function. Trends Genet., 2015, 31(6), 290-299.
[http://dx.doi.org/10.1016/j.tig.2015.02.008] [PMID: 25812926]
Stitzel, M.L.; Sethupathy, P.; Pearson, D.S.; Chines, P.S.; Song, L.; Erdos, M.R.; Welch, R.; Parker, S.C.J.; Boyle, A.P.; Scott, L.J.; Margulies, E.H.; Boehnke, M.; Furey, T.S.; Crawford, G.E.; Collins, F.S. Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci. Cell Metab., 2010, 12(5), 443-455.
[http://dx.doi.org/10.1016/j.cmet.2010.09.012] [PMID: 21035756]
Voisin, S.; Almén, M.S.; Zheleznyakova, G.Y.; Lundberg, L.; Zarei, S.; Castillo, S.; Eriksson, F.E.; Nilsson, E.K.; Blü-her, M.; Böttcher, Y. Many Obesity-Associated SNPs Strongly Associate with DNA Methylation Changes at Proximal Pro-moters and Enhancers. Genome Med., 2015, 7(1), 1-16.
[http://dx.doi.org/10.1186/s13073-015-0225-4] [PMID: 25606059]
Kycia, I.; Wolford, B.N.; Huyghe, J.R.; Fuchsberger, C.; Vadlamudi, S.; Kursawe, R.; Welch, R.P.; Albanus, R. d’Oliveira; Uyar, A.; Khetan, S. A Common Type 2 Diabetes Risk Variant Potentiates Activity of an Evolutionarily Con-served Islet Stretch Enhancer and Increases C2CD4A and C2CD4B Expression. Am. J. Hum. Genet., 2018, 102(4), 620-635.
[http://dx.doi.org/10.1016/j.ajhg.2018.02.020] [PMID: 29625024]
Lawlor, N.; Khetan, S.; Ucar, D.; Stitzel, M.L. Genomics of Islet (Dys)function and Type 2 Diabetes. Trends Genet., 2017, 33(4), 244-255.
[http://dx.doi.org/10.1016/j.tig.2017.01.010] [PMID: 28245910]

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Year: 2019
Published on: 03 September, 2019
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DOI: 10.2174/1871530319666190301145545
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