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Diabetologia
Published in: Diabetologia 1/2018

Open Access 01-01-2018 | Review

Epigenetics in diabetic nephropathy, immunity and metabolism

Authors: Samuel T. Keating, Janna A. van Diepen, Niels P. Riksen, Assam El-Osta

Published in: Diabetologia | Issue 1/2018

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Abstract

When it comes to the epigenome, there is a fine line between clarity and confusion—walk that line and you will discover another fascinating level of transcription control. With the genetic code representing the cornerstone of rules for information that is encoded to proteins somewhere above the genome level there is a set of rules by which chemical information is also read. These epigenetic modifications show a different side of the genetic code that is diverse and regulated, hence modifying genetic transcription transiently, ranging from short- to long-term alterations. While this complexity brings exquisite control it also poses a formidable challenge to efforts to decode mechanisms underlying complex disease. Recent technological and computational advances have improved unbiased acquisition of epigenomic patterns to improve our understanding of the complex chromatin landscape. Key to resolving distinct chromatin signatures of diabetic complications is the identification of the true physiological targets of regulatory proteins, such as reader proteins that recognise, writer proteins that deposit and eraser proteins that remove specific chemical moieties. But how might a diverse group of proteins regulate the diabetic landscape from an epigenomic perspective? Drawing from an ever-expanding compendium of experimental and clinical studies, this review details the current state-of-play and provides a perspective of chromatin-dependent mechanisms implicated in diabetic complications, with a special focus on diabetic nephropathy. We hypothesise a codified signature of the diabetic epigenome and provide examples of prime candidates for chemical modification. As for the pharmacological control of epigenetic marks, we explore future strategies to expedite and refine the search for clinically relevant discoveries. We also consider the challenges associated with therapeutic strategies targeting epigenetic pathways.
Appendix
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Literature
1.
Thomas MC, Groop PH, Tryggvason K (2012) Towards understanding the inherited susceptibility for nephropathy in diabetes. Curr Opin Nephrol Hypertens 21:195–202PubMedCrossRef
2.
Nathan DM, Cleary PA, Backlund JY et al (2005) Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643–2653PubMedCrossRef
3.
DCCT/EDIC The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group (2000) Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 342:381–389CrossRef
4.
Hammes HP, Klinzing I, Wiegand S, Bretzel RG, Cohen AM, Federlin K (1993) Islet transplantation inhibits diabetic retinopathy in the sucrose-fed diabetic Cohen rat. Invest Ophthalmol Vis Sci 34:2092–2096PubMed
5.
Roy S, Sala R, Cagliero E, Lorenzi M (1990) Overexpression of fibronectin induced by diabetes or high glucose: phenomenon with a memory. Proc Natl Acad Sci U S A 87:404–408PubMedPubMedCentralCrossRef
6.
Engerman RL, Kern TS (1987) Progression of incipient diabetic retinopathy during good glycemic control. Diabetes 36:808–812PubMedCrossRef
7.
Gaede P, Oellgaard J, Carstensen B et al (2016) Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial. Diabetologia 59:2298–2307PubMedPubMedCentralCrossRef
8.
Hayward RA, Reaven PD, Wiitala WL et al (2015) Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med 372:2197–2206PubMedCrossRef
9.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577–1589PubMedCrossRef
10.
11.
Mannucci E, Dicembrini I, Lauria A, Pozzilli P (2013) Is glucose control important for prevention of cardiovascular disease in diabetes? Diabetes Care 36(Suppl 2):S259–S263PubMedPubMedCentralCrossRef
12.
13.
Sasso FC, Chiodini P, Carbonara O et al (2012) High cardiovascular risk in patients with type 2 diabetic nephropathy: the predictive role of albuminuria and glomerular filtration rate. The NID-2 Prospective Cohort Study. Nephrol Dial Transplant 27:2269–2274PubMedCrossRef
14.
Chawla A, Chawla R, Jaggi S (2016) Microvasular and macrovascular complications in diabetes mellitus: distinct or continuum? Indian J Endocrinol Metab 20:546–551PubMedPubMedCentralCrossRef
15.
The Diabetes Control and Complications Trial Research Group (1997) Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. Diabetes 46:1829–1839CrossRef
16.
Quinn M, Angelico MC, Warram JH, Krolewski AS (1996) Familial factors determine the development of diabetic nephropathy in patients with IDDM. Diabetologia 39:940–945PubMedCrossRef
17.
Seaquist ER, Goetz FC, Rich S, Barbosa J (1989) Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320:1161–1165PubMedCrossRef
18.
Ma RC, Cooper ME (2017) Genetics of diabetic kidney disease—from the worst of nightmares to the light of dawn? J Am Soc Nephrol 28:389–393PubMedCrossRef
19.
Sandholm N, Van Zuydam N, Ahlqvist E et al (2017) The genetic landscape of renal complications in type 1 diabetes. J Am Soc Nephrol 28:557–574PubMedCrossRef
20.
Flavahan WA, Drier Y, Liau BB et al (2016) Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529:110–114PubMedCrossRef
21.
22.
Dubois-Chevalier J, Oger F, Dehondt H et al (2014) A dynamic CTCF chromatin binding landscape promotes DNA hydroxymethylation and transcriptional induction of adipocyte differentiation. Nucleic Acids Res 42:10943–10959PubMedPubMedCentralCrossRef
23.
Heintzman ND, Stuart RK, Hon G et al (2007) Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39:311–318PubMedCrossRef
24.
El-Osta A, Brasacchio D, Yao D et al (2008) Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med 205:2409–2417PubMedPubMedCentralCrossRef
25.
26.
Brasacchio D, Okabe J, Tikellis C et al (2009) Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes 58:1229–1236PubMedPubMedCentralCrossRef
27.
28.
29.
McKinsey TA (2012) Therapeutic potential for HDAC inhibitors in the heart. Annu Rev Pharmacol Toxicol 52:303–319PubMedCrossRef
30.
Paneni F, Costantino S, Battista R et al (2015) Adverse epigenetic signatures by histone methyltransferase Set7 contribute to vascular dysfunction in patients with type 2 diabetes mellitus. Circ Cardiovasc Genet 8:150–158PubMedCrossRef
31.
Miao F, Chen Z, Genuth S et al (2014) Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes. Diabetes 63:1748–1762PubMedPubMedCentralCrossRef
32.
33.
Yoshizawa C, Kobayashi Y, Ikeuchi Y et al (2016) Congenital nephrotic syndrome with a novel NPHS1 mutation. Pediatr Int 58:1211–1215PubMedCrossRef
34.
Yamaguchi Y, Iwano M, Suzuki D et al (2009) Epithelial-mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy. Am J Kidney Dis 54:653–664PubMedCrossRef
35.
36.
Petermann AT, Pippin J, Krofft R et al (2004) Viable podocytes detach in experimental diabetic nephropathy: potential mechanism underlying glomerulosclerosis. Nephron Exp Nephrol 98:e114–e123PubMedCrossRef
37.
Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872PubMedCrossRef
38.
Hayashi K, Sasamura H, Nakamura M et al (2014) KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria. J Clin Invest 124:2523–2537PubMedPubMedCentralCrossRef
39.
Ristola M, Arpiainen S, Saleem MA, Holthofer H, Lehtonen S (2012) Transcription of nephrin-Neph3 gene pair is synergistically activated by WT1 and NF-kappaB and silenced by DNA methylation. Nephrol Dial Transplant 27:1737–1745PubMedCrossRef
40.
Siddiqi FS, Majumder S, Thai K et al (2016) The histone methyltransferase enzyme enhancer of zeste homolog 2 protects against podocyte oxidative stress and renal injury in diabetes. J Am Soc Nephrol 27:2021–2034PubMedCrossRef
41.
De Marinis Y, Cai M, Bompada P et al (2016) Epigenetic regulation of the thioredoxin-interacting protein (TXNIP) gene by hyperglycemia in kidney. Kidney Int 89:342–353PubMedCrossRef
42.
Bock F, Shahzad K, Wang H et al (2013) Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc. Proc Natl Acad Sci U S A 110:648–653PubMedCrossRef
43.
Paneni F, Mocharla P, Akhmedov A et al (2012) Gene silencing of the mitochondrial adaptor p66Shc suppresses vascular hyperglycemic memory in diabetes. Circ Res 111:278–289PubMedCrossRef
44.
Zhou S, Chen HZ, Wan YZ et al (2011) Repression of P66Shc expression by SIRT1 contributes to the prevention of hyperglycemia-induced endothelial dysfunction. Circ Res 109:639–648PubMedCrossRef
45.
Tang SC, Lai KN (2012) The pathogenic role of the renal proximal tubular cell in diabetic nephropathy. Nephrol Dial Transplant 27:3049–3056PubMedCrossRef
46.
Marumo T, Yagi S, Kawarazaki W et al (2015) Diabetes induces aberrant DNA methylation in the proximal tubules of the kidney. J Am Soc Nephrol 26:2388–2397PubMedPubMedCentralCrossRef
47.
Hasegawa K, Wakino S, Simic P et al (2013) Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nat Med 19:1496–1504PubMedPubMedCentralCrossRef
48.
Reddy MA, Sumanth P, Lanting L et al (2014) Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic db/db mice. Kidney Int 85:362–373PubMedCrossRef
49.
Furuta T, Saito T, Ootaka T et al (1993) The role of macrophages in diabetic glomerulosclerosis. Am J Kidney Dis 21:480–485PubMedCrossRef
50.
Sassy-Prigent C, Heudes D, Mandet C et al (2000) Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. Diabetes 49:466–475PubMedCrossRef
51.
Wada J, Makino H (2016) Innate immunity in diabetes and diabetic nephropathy. Nat Rev Nephrol 12:13–26PubMedCrossRef
52.
Tanaka M, Masuda S, Matsuo Y et al (2016) Hyperglycemia and inflammatory property of circulating monocytes are associated with inflammatory property of carotid plaques in patients undergoing carotid endarterectomy. J Atheroscler Thromb 23:1212–1221PubMedPubMedCentralCrossRef
53.
Kon V, Linton MF, Fazio S (2011) Atherosclerosis in chronic kidney disease: the role of macrophages. Nat Rev Nephrol 7:45–54PubMedCrossRef
54.
Chen Z, Miao F, Paterson AD et al (2016) Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort. Proc Natl Acad Sci U S A 113:E3002–E3011PubMedPubMedCentralCrossRef
55.
56.
Kleinnijenhuis J, Quintin J, Preijers F et al (2012) Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A 109:17537–17542PubMedPubMedCentralCrossRef
57.
Quintin J, Saeed S, Martens JH et al (2012) Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12:223–232PubMedCrossRef
58.
Saeed S, Quintin J, Kerstens HH et al (2014) Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345:1251086PubMedPubMedCentralCrossRef
59.
Novakovic B, Habibi E, Wang SY et al (2016) Beta-glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell 167:1354–1368.e1314PubMedCrossRef
60.
Ostuni R, Piccolo V, Barozzi I et al (2013) Latent enhancers activated by stimulation in differentiated cells. Cell 152:157–171PubMedCrossRef
61.
Blok BA, Arts RJ, van Crevel R, Benn CS, Netea MG (2015) Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines. J Leukoc Biol 98:347–356PubMedCrossRef
62.
Bekkering S, Joosten LA, van der Meer JW, Netea MG, Riksen NP (2013) Trained innate immunity and atherosclerosis. Curr Opin Lipidol 24:487–492PubMedCrossRef
63.
Christ A, Bekkering S, Latz E, Riksen NP (2016) Long-term activation of the innate immune system in atherosclerosis. Semin Immunol 28:384–393PubMedCrossRef
64.
Bekkering S, Quintin J, Joosten LA, van der Meer JW, Netea MG, Riksen NP (2014) Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler Thromb Vasc Biol 34:1731–1738PubMedCrossRef
65.
van der Valk FM, Bekkering S, Kroon J et al (2016) Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation 134:611–624PubMedPubMedCentralCrossRef
66.
Yan SF, Ramasamy R, Schmidt AM (2008) Mechanisms of disease: advanced glycation end-products and their receptor in inflammation and diabetes complications. Nat Clin Pract Endocrinol Metab 4:285–293PubMedCrossRef
67.
Shanmugam N, Reddy MA, Guha M, Natarajan R (2003) High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells. Diabetes 52:1256–1264PubMedCrossRef
68.
van Diepen JA, Thiem K, Stienstra R, Riksen NP, Tack CJ, Netea MG (2016) Diabetes propels the risk for cardiovascular disease: sweet monocytes becoming aggressive? Cell Mol Life Sci 73:4675–4684PubMedPubMedCentralCrossRef
69.
Cheng SC, Quintin J, Cramer RA et al (2014) mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345:1250684PubMedPubMedCentralCrossRef
70.
Arts RJ, Novakovic B, Ter Horst R et al (2016) Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab 24:807–819PubMedCrossRef
71.
Donohoe DR, Collins LB, Wali A, Bigler R, Sun W, Bultman SJ (2012) The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol Cell 48:612–626PubMedPubMedCentralCrossRef
72.
Cheng SC, Joosten LA, Netea MG (2014) The interplay between central metabolism and innate immune responses. Cytokine Growth Factor Rev 25:707–713PubMedCrossRef
73.
74.
75.
de Oliveira AA, de Oliveira TF, Bobadilla LL et al (2017) Sustained kidney biochemical derangement in treated experimental diabetes: a clue to metabolic memory. Sci Rep 7:40544PubMedPubMedCentralCrossRef
76.
Sharma A (2017) Transgenerational epigenetics: integrating soma to germline communication with gametic inheritance. Mech Ageing Dev 163:15–22PubMedCrossRef
77.
Cropley JE, Eaton SA, Aiken A et al (2016) Male-lineage transmission of an acquired metabolic phenotype induced by grand-paternal obesity. Mol Metab 5:699–708PubMedPubMedCentralCrossRef
78.
Khurana I, Kaspi A, Ziemann M et al (2016) DNA methylation regulates hypothalamic gene expression linking parental diet during pregnancy to the offspring’s risk of obesity in Psammomys obesus. Int J Obes 40:1079–1088CrossRef
79.
Bell CG, Teschendorff AE, Rakyan VK, Maxwell AP, Beck S, Savage DA (2010) Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus. BMC Med Genet 3:33
80.
Sapienza C, Lee J, Powell J et al (2011) DNA methylation profiling identifies epigenetic differences between diabetes patients with ESRD and diabetes patients without nephropathy. Epigenetics 6:20–28PubMedCrossRef
81.
Tregouet DA, Groop PH, McGinn S et al (2008) G/T substitution in intron 1 of the UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes. Diabetes 57:2843–2850PubMedPubMedCentralCrossRef
82.
Miao F, Wu X, Zhang L, Riggs AD, Natarajan R (2008) Histone methylation patterns are cell-type specific in human monocytes and lymphocytes and well maintained at core genes. J Immunol 180:2264–2269PubMedPubMedCentralCrossRef
83.
Reinius LE, Acevedo N, Joerink M et al (2012) Differential DNA methylation in purified human blood cells: implications for cell lineage and studies on disease susceptibility. PLoS One 7:e41361PubMedPubMedCentralCrossRef
84.
85.
Pirola L, Balcerczyk A, Tothill RW et al (2011) Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells. Genome Res 21:1601–1615PubMedPubMedCentralCrossRef
86.
87.
Richmond RC, Sharp GC, Ward ME et al (2016) DNA methylation and BMI: investigating identified methylation sites at HIF3A in a causal framework. Diabetes 65:1231–1244PubMedPubMedCentralCrossRef
88.
Rakyan VK, Beyan H, Down TA et al (2011) Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis. PLoS Genet 7:e1002300PubMedPubMedCentralCrossRef
89.
Valencia-Morales Mdel P, Zaina S, Heyn H et al (2015) The DNA methylation drift of the atherosclerotic aorta increases with lesion progression. BMC Med Genet 8:7
90.
Lewis A, Murrell A (2004) Genomic imprinting: CTCF protects the boundaries. Curr Biol 14:R284–R286PubMedCrossRef
91.
Kanduri C, Pant V, Loukinov D et al (2000) Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive. Curr Biol 10:853–856PubMedCrossRef
92.
Demars J, Shmela ME, Khan AW et al (2014) Genetic variants within the second intron of the KCNQ1 gene affect CTCF binding and confer a risk of Beckwith-Wiedemann syndrome upon maternal transmission. J Med Genet 51:502–511PubMedCrossRef
93.
Fedoriw AM, Stein P, Svoboda P, Schultz RM, Bartolomei MS (2004) Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting. Science 303:238–240PubMedCrossRef
94.
Stitzel ML, Sethupathy P, Pearson DS et al (2010) Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci. Cell Metab 12:443–455PubMedPubMedCentralCrossRef
95.
El-Osta A, Kantharidis P, Zalcberg JR, Wolffe AP (2002) Precipitous release of methyl-CpG binding protein 2 and histone deacetylase 1 from the methylated human multidrug resistance gene (MDR1) on activation. Mol Cell Biol 22:1844–1857PubMedPubMedCentralCrossRef
96.
Harikrishnan KN, Chow MZ, Baker EK et al (2005) Brahma links the SWI/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing. Nat Genet 37:254–264PubMedCrossRef
97.
McCarthy MI (2015) Genomic medicine at the heart of diabetes management. Diabetologia 58:1725–1729PubMedCrossRef
98.
King-Himmelreich TS, Schramm S, Wolters MC et al (2016) The impact of endurance exercise on global and AMPK gene-specific DNA methylation. Biochem Biophys Res Commun 474:284–290PubMedCrossRef
99.
Hoeksema MA, Gijbels MJ, Van den Bossche J et al (2014) Targeting macrophage histone deacetylase 3 stabilizes atherosclerotic lesions. EMBO Mol Med 6:1124–1132PubMedPubMedCentralCrossRef
100.
Zampetaki A, Zeng L, Margariti A et al (2010) Histone deacetylase 3 is critical in endothelial survival and atherosclerosis development in response to disturbed flow. Circulation 121:132–142PubMedCrossRef
101.
102.
Okabe J, Orlowski C, Balcerczyk A et al (2012) Distinguishing hyperglycemic changes by Set7 in vascular endothelial cells. Circ Res 110:1067–1076PubMedCrossRef
103.
Keating ST, Ziemann M, Okabe J, Khan AW, Balcerczyk A, El-Osta A (2014) Deep sequencing reveals novel Set7 networks. Cell Mol Life Sci 71:4471–4486PubMedCrossRef
104.
Lian Y, Wang J, Feng J et al (2016) Long non-coding RNA IRAIN suppresses apoptosis and promotes proliferation by binding to LSD1 and EZH2 in pancreatic cancer. Tumour Biol 37:14929–14937PubMedCrossRef
105.
Battistelli C, Cicchini C, Santangelo L et al (2017) The snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition. Oncogene 36:942–955PubMedCrossRef
106.
Yuan H, Reddy MA, Deshpande S et al (2016) Epigenetic histone modifications involved in profibrotic gene regulation by 12/15-lipoxygenase and its oxidized lipid products in diabetic nephropathy. Antioxid Redox Signal 24:361–375PubMedPubMedCentralCrossRef
107.
Syreeni A, El-Osta A, Forsblom C et al (2011) Genetic examination of SETD7 and SUV39H1/H2 methyltransferases and the risk of diabetes complications in patients with type 1 diabetes. Diabetes 60:3073–3080PubMedPubMedCentralCrossRef
108.
109.
Villeneuve LM, Reddy MA, Lanting LL, Wang M, Meng L, Natarajan R (2008) Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes. Proc Natl Acad Sci U S A 105:9047–9052PubMedPubMedCentralCrossRef
110.
Hardikar AA, Satoor SN, Karandikar MS et al (2015) Multigenerational undernutrition increases susceptibility to obesity and diabetes that is not reversed after dietary recuperation. Cell Metab 22:312–319PubMedCrossRef
111.
Chen H, Gu X, Su IH et al (2009) Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes Dev 23:975–985PubMedPubMedCentralCrossRef
112.
Sakai M, Tujimura-Hayakawa T, Yagi T et al (2016) The GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch. Nat Commun 7:13147PubMedPubMedCentralCrossRef
113.
Vecellio M, Spallotta F, Nanni S et al (2014) The histone acetylase activator pentadecylidenemalonate 1b rescues proliferation and differentiation in the human cardiac mesenchymal cells of type 2 diabetic patients. Diabetes 63:2132–2147PubMedCrossRef
114.
Gallagher KA, Joshi A, Carson WF et al (2015) Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes. Diabetes 64:1420–1430PubMedCrossRef
115.
116.
Sathishkumar C, Prabu P, Balakumar M et al (2016) Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes. Clin Epigenetics 8:125PubMedPubMedCentralCrossRef
117.
Wang X, Liu J, Zhen J et al (2014) Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy. Kidney Int 86:712–725PubMedCrossRef
118.
Daneshpajooh M, Bacos K, Bysani M et al (2017) HDAC7 is overexpressed in human diabetic islets and impairs insulin secretion in rat islets and clonal beta cells. Diabetologia 60:116–125PubMedCrossRef
119.
Bell AC, Felsenfeld G (2000) Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405:482–485PubMedCrossRef
120.
Barres R, Osler ME, Yan J et al (2009) Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density. Cell Metab 10:189–198PubMedCrossRef
121.
Pennarossa G, Maffei S, Campagnol M, Tarantini L, Gandolfi F, Brevini TA (2013) Brief demethylation step allows the conversion of adult human skin fibroblasts into insulin-secreting cells. Proc Natl Acad Sci U S A 110:8948–8953PubMedPubMedCentralCrossRef
122.
Volkmar M, Dedeurwaerder S, Cunha DA et al (2012) DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J 31:1405–1426PubMedPubMedCentralCrossRef
123.
Ling C, Del Guerra S, Lupi R et al (2008) Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 51:615–622PubMedPubMedCentralCrossRef
124.
Kirchner H, Sinha I, Gao H et al (2016) Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients. Mol Metab 5:171–183PubMedPubMedCentralCrossRef
125.
Babu M, Durga Devi T, Makinen P et al (2015) Differential promoter methylation of macrophage genes is associated with impaired vascular growth in ischemic muscles of hyperlipidemic and type 2 diabetic mice: genome-wide promoter methylation study. Circ Res 117:289–299PubMedCrossRef
126.
Radford EJ, Ito M, Shi H et al (2014) In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345:1255903PubMedPubMedCentralCrossRef
127.
Dayeh T, Volkov P, Salo S et al (2014) 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 10:e1004160PubMedPubMedCentralCrossRef
128.
Yang BT, Dayeh TA, Volkov PA et al (2012) Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes. Mol Endocrinol 26:1203–1212PubMedPubMedCentralCrossRef
129.
Park JH, Stoffers DA, Nicholls RD, Simmons RA (2008) Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 118:2316–2324PubMedPubMedCentralCrossRef
130.
Multhaup ML, Seldin MM, Jaffe AE et al (2015) Mouse-human experimental epigenetic analysis unmasks dietary targets and genetic liability for diabetic phenotypes. Cell Metab 21:138–149PubMedPubMedCentralCrossRef
131.
Kalani A, Kamat PK, Tyagi N (2015) Diabetic stroke severity: epigenetic remodeling and neuronal, glial, and vascular dysfunction. Diabetes 64:4260–4271PubMedPubMedCentralCrossRef
132.
Volkov P, Bacos K, Ofori JK et al (2017) Whole-genome bisulfite sequencing of human pancreatic islets reveals novel differentially methylated regions in type 2 diabetes pathogenesis. Diabetes 66:1074–1085PubMedCrossRef
133.
Soriano-Tarraga C, Jimenez-Conde J, Giralt-Steinhauer E et al (2016) Epigenome-wide association study identifies TXNIP gene associated with type 2 diabetes mellitus and sustained hyperglycemia. Hum Mol Genet 25:609–619PubMedCrossRef
134.
135.
Orozco LD, Morselli M, Rubbi L et al (2015) Epigenome-wide association of liver methylation patterns and complex metabolic traits in mice. Cell Metab 21:905–917PubMedPubMedCentralCrossRef
136.
Gu T, Falhammar H, Gu HF, Brismar K (2014) Epigenetic analyses of the insulin-like growth factor binding protein 1 gene in type 1 diabetes and diabetic nephropathy. Clin Epigenetics 6:10PubMedPubMedCentralCrossRef
137.
Ruchat SM, Houde AA, Voisin G et al (2013) Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases. Epigenetics 8:935–943PubMedPubMedCentralCrossRef
138.
Mudry JM, Lassiter DG, Nylen C et al (2016) Insulin and glucose alter death-associated protein kinase 3 (DAPK3) DNA methylation in human skeletal muscle. Diabetes 66:651–662PubMedCrossRef
139.
Volkov P, Olsson AH, Gillberg L et al (2016) A genome-wide mQTL analysis in human adipose tissue identifies genetic variants associated with DNA methylation, gene expression and metabolic traits. PLoS One 11:e0157776PubMedPubMedCentralCrossRef
140.
Clarke-Harris R, Wilkin TJ, Hosking J et al (2014) PGC1alpha promoter methylation in blood at 5-7 years predicts adiposity from 9 to 14 years (EarlyBird 50). Diabetes 63:2528–2537PubMedCrossRef
141.
Zeng L, Kanwar YS, Amro N et al (2003) Epigenetic and genetic analysis of p16 in dermal fibroblasts from type 1 diabetic patients with nephropathy. Kidney Int 63:2094–2102PubMedCrossRef
142.
Paul DS, Teschendorff AE, Dang MA et al (2016) Increased DNA methylation variability in type 1 diabetes across three immune effector cell types. Nat Commun 7:13555PubMedPubMedCentralCrossRef
143.
Reichetzeder C, Dwi Putra SE, Pfab T et al (2016) Increased global placental DNA methylation levels are associated with gestational diabetes. Clin Epigenetics 8:82PubMedPubMedCentralCrossRef
144.
Bacos K, Gillberg L, Volkov P et al (2016) Blood-based biomarkers of age-associated epigenetic changes in human islets associate with insulin secretion and diabetes. Nat Commun 7:11089PubMedPubMedCentralCrossRef
145.
Ronn T, Volkov P, Gillberg L et al (2015) Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood. Hum Mol Genet 24:3792–3813PubMed
146.
147.
Nilsson E, Jansson PA, Perfilyev A et al (2014) Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes. Diabetes 63:2962–2976PubMedCrossRef
148.
El Hajj N, Pliushch G, Schneider E et al (2013) Metabolic programming of MEST DNA methylation by intrauterine exposure to gestational diabetes mellitus. Diabetes 62:1320–1328PubMedPubMedCentralCrossRef
149.
Ling C, Poulsen P, Simonsson S et al (2007) Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. J Clin Invest 117:3427–3435PubMedPubMedCentralCrossRef
150.
Sun M, Song MM, Wei B et al (2016) 5-Hydroxymethylcytosine-mediated alteration of transposon activity associated with the exposure to adverse in utero environments in human. Hum Mol Genet 25:2208–2219PubMedPubMedCentralCrossRef
151.
Frayling TM, Timpson NJ, Weedon MN et al (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894PubMedPubMedCentralCrossRef
152.
Fischer J, Koch L, Emmerling C et al (2009) Inactivation of the Fto gene protects from obesity. Nature 458:894–898PubMedCrossRef
153.
154.
Wu W, Feng J, Jiang D et al (2017) AMPK regulates lipid accumulation in skeletal muscle cells through FTO-dependent demethylation of N6-methyladenosine. Sci Rep 7:41606PubMedPubMedCentralCrossRef
155.
Shen F, Huang W, Huang JT et al (2015) Decreased N 6-methyladenosine in peripheral blood RNA from diabetic patients is associated with FTO expression rather than ALKBH5. J Clin Endocrinol Metab 100:E148–E154PubMedCrossRef
Metadata
Title
Epigenetics in diabetic nephropathy, immunity and metabolism
Authors
Samuel T. Keating
Janna A. van Diepen
Niels P. Riksen
Assam El-Osta
Publication date
01-01-2018
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 1/2018
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-017-4490-1

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