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Current Diabetes Reports
Published in: Current Diabetes Reports 5/2013

01-10-2013 | Pathogenesis of Type 1 Diabetes (D Dabelea, Section Editor)

Epigenetic Regulation of Pancreatic Islets

Author: Cecile Haumaitre

Published in: Current Diabetes Reports | Issue 5/2013

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Abstract

Epigenetic mechanisms, including DNA methylation, histone modifications, and noncoding RNA expression, contribute to regulate islet cell development and function. Indeed, epigenetic mechanisms were recently shown to be involved in the control of endocrine cell fate decision, islet differentiation, β-cell identity, proliferation, and mature function. Epigenetic mechanisms can also contribute to the pathogenesis of complex diseases. Emerging knowledge regarding epigenetic mechanisms suggest that they may be involved in β-cell dysfunction and pathogenesis of diabetes. Epigenetic mechanisms could predispose to the diabetic phenotype such as decline of β-cell proliferation ability and β-cell failure, and account for complications associated with diabetes. Better understanding of epigenetic landscapes of islet differentiation and function may be useful to improve β-cell differentiation protocols and discover novel therapeutic targets for prevention and treatment of diabetes.
Literature
1.
Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355:1318–30.PubMedCrossRef
2.
Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes & Dev. 2009;23:781–3.CrossRef
3.
Bird A. DNA methylation patterns and epigenetic memory. Genes & Dev. 2002;16:6–21.CrossRef
4.
Karnik SK, Chen H, McLean GW, Heit JJ, Gu X, Zhang AY, et al. Menin controls growth of pancreatic beta-cells in pregnant mice and promotes gestational diabetes mellitus. Science. 2007;318:806–9.PubMedCrossRef
5.
Park JH, Stoffers DA, Nicholls RD, Simmons RA. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest. 2008;118:2316–24.PubMedCrossRef
6.
Yang BT, Dayeh TA, Volkov PA, Kirkpatrick CL, Malmgren S, Jing X, et al. Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes. Molecular Endocrinol. 2012;26:1203–12.CrossRef
7.
Collombat P, Hecksher-Sorensen J, Krull J, Berger J, Riedel D, Herrera PL, et al. Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression. J Clin Invest. 2007;117:961–70.PubMedCrossRef
8.
Thorel F, Nepote V, Avril I, Kohno K, Desgraz R, Chera S, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature. 2010;464:1149–54.PubMedCrossRef
9.
Papizan JB, Singer RA, Tschen SI, Dhawan S, Friel JM, Hipkens SB, et al. Nkx2.2 repressor complex regulates islet beta-cell specification and prevents beta-to-alpha-cell reprogramming. Genes & Dev. 2011;25:2291–305.CrossRef
10.
•• Dhawan S, Georgia S, Tschen SI, Fan G, Bhushan A. Pancreatic beta cell identity is maintained by DNA methylation-mediated repression of Arx. Dev Cell. 2011;20:419–29. This article reported that deletion of the Dnmt1 DNA methyltransferase gene in pancreatic insulin-producing cells makes these cells convert into glucagon-producing cells. This suggests that epigenetic reprogramming of cell types with shared developmental history may be used to redirect cell fates and be an effective strategy for pancreatic β cell-replacement therapies for diabetes. PubMedCrossRef
11.
Van Arensbergen J, Garcia-Hurtado J, Maestro MA, et al. Ring1b bookmarks genes in pancreatic embryonic progenitors for repression in adult beta cells. Genes & Dev. 2013;27:52–63.CrossRef
12.
Bruggeman SW, Valk-Lingbeek ME, van der Stoop PP, Jacobs JJ, Kieboom K, et al. Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes & Dev. 2005;19:1438–43.CrossRef
13.
Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature. 2006;443:453–7.PubMedCrossRef
14.
Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316:1331–6.CrossRef
15.
Dhawan S, Tschen SI, Bhushan A. Bmi-1 regulates the Ink4a/Arf locus to control pancreatic beta-cell proliferation. Genes & Dev. 2009;23:906–11.CrossRef
16.
Chen H, Gu X, Su IH, Bottino R, Contreras JL, Tarakhovsky A, et al. Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes & Dev. 2009;23:975–85.CrossRef
17.
van Arensbergen J, Garcia-Hurtado J, Moran I, Maestro MA, Xu X, Van de Casteele M. Derepression of Polycomb targets during pancreatic organogenesis allows insulin-producing beta-cells to adopt a neural gene activity program. Genome Res. 2010;20:722–32.PubMedCrossRef
18.
Bramswig NC, Everett LJ, Schug J, Dorrell C, Liu C, Luo Y, et al. Epigenomic plasticity enables human pancreatic α to β cell reprogramming. J Clin Invest. 2013;123:1275–84.PubMedCrossRef
19.
Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi PG, et al. A map of open chromatin in human pancreatic islets. Nature Genet. 2010;42:255–9.PubMedCrossRef
20.
Bhandare R, Schug J, Le Lay J, Fox A, Smirnova O, Liu C, et al. Genome-wide analysis of histone modifications in human pancreatic islets. Genome Res. 2010;20:428–33.PubMedCrossRef
21.
Stitzel ML, Sethupathy P, Pearson DS, Chines PS, Song L, et al. Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci. Cell Metab. 2010;12:443–55.PubMedCrossRef
22.
Volkmar M, Dedeurwaerder S, Cunha DA, Ndlovu MN, Defrance M, et al. DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J. 2012;31:1405–26.PubMedCrossRef
23.
Keating ST, El-Osta A. Epigenetic changes in diabetes. Clinical Genet. 2013;[Epub ahead of print].
24.
Miao F, Smith DD, Zhang L, Min A, Feng W, Natarajan R. Lymphocytes from patients with type 1 diabetes display a distinct profile of chromatin histone H3 lysine 9 dimethylation: an epigenetic study in diabetes. Diabetes. 2008;57:3189–98.PubMedCrossRef
25.
Pirola L, Balcerczyk A, Tothill RW, et al. Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells. Genome Res. 2011;21:1601–15.PubMedCrossRef
26.
Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet. 2009;10:32–42.PubMedCrossRef
27.
Haumaitre C, Lenoir O, Scharfmann R. Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Mol Cell Biol. 2008;28:6373–83.PubMedCrossRef
28.
Haumaitre C, Lenoir O, Scharfmann R. Directing cell differentiation with small-molecule histone deacetylase inhibitors: the example of promoting pancreatic endocrine cells. Cell Cycle. 2009;8:536–44.PubMedCrossRef
29.
Lenoir O, Flosseau K, Ma FX, Blondeau B, Mai A, Bassel-Duby R, et al. Specific control of pancreatic endocrine beta- and delta-cell mass by class IIa histone deacetylases HDAC4, HDAC5, and HDAC9. Diabetes. 2011;60:2861–71.PubMedCrossRef
30.
Nerup J, Pociot F, European Consortium for I.S. A genomewide scan for type 1-diabetes susceptibility in Scandinavian families: identification of new loci with evidence of interactions. Am J Hum Gen. 2001;69:1301–13.CrossRef
31.
Xiang K, Wang Y, Zheng T, Jia W, Li J, Chen L, et al. Genome-wide search for type 2 diabetes/impaired glucose homeostasis susceptibility genes in the Chinese: significant linkage to chromosome 6q21-q23 and chromosome 1q21-q24. Diabetes. 2004;53:228–34.PubMedCrossRef
32.
Larsen L, Tonnesen M, Ronn SG, Storling J, Jorgensen S, Mascagni P, et al. Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells. Diabetologia. 2007;50:779–89.PubMedCrossRef
33.
Lundh M, Christensen DP, Rasmussen DN, Mascagni P, Dinarello CA, Billestrup N, et al. Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines. Diabetologia. 2010;53:2569–78.PubMedCrossRef
34.
Susick L, Senanayake T, Veluthakal R, Woste PM, Kowluru A. A novel histone deacetylase inhibitor prevents IL-1beta induced metabolic dysfunction in pancreatic beta-cells. J Cell Mol Med. 2009;13:1877–85.PubMedCrossRef
35.
Susick L, Veluthakal R, Suresh MV, Hadden T, Kowluru A. Regulatory roles for histone deacetylation in IL-1beta-induced nitric oxide release in pancreatic beta-cells. J Cell Mol Med. 2008;12:1571–83.PubMedCrossRef
36.
• Lewis EC, Blaabjerg L, Storling J, et al. The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet beta cells in vivo and in vitro. Mol Med. 2011;17:369–77. This article demonstrates that at clinically relevant doses, the orally active HDAC inhibitor ITF2357 favors survival of β cells exposed to inflammatory challenges. This suggests that oral ITF2357 would be an effective candidate for reducing inflammation in the islets in type 1 diabetes. PubMedCrossRef
37.
Chou DH, Holson EB, Wagner FF, Tang AJ, Maglathlin RL, Lewis TA, et al. Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chem Biol. 2012;19:669–73.PubMedCrossRef
38.
• Kubicek S, Gilbert JC, Fomina-Yadlin D, et al. Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells. Proc Natl Acad Sci USA. 2012;109:5364–9. This article provides a measure of the genome-wide transcriptional effects of 29 compounds in pancreatic α- and β-cell lines. It shows that inhibiting chromatin-modifying enzymes with small molecules can activate very specific pathways, reinforcing the importance of novel small molecules development. PubMedCrossRef
39.
40.
Poy MN, Spranger M, Stoffel M. MicroRNAs and the regulation of glucose and lipid metabolism. Diabetes Obes Metab. 2007;9 Suppl 2:67–73.PubMedCrossRef
41.
Lynn FC, Skewes-Cox P, Kosaka Y, McManus MT, Harfe BD, German MS. MicroRNA expression is required for pancreatic islet cell genesis in the mouse. Diabetes. 2007;56:2938–45.PubMedCrossRef
42.
Kalis M, Bolmeson C, Esguerra JL, Gupta S, Edlund A, et al. Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus. PloS One. 2011;6:e29166.PubMedCrossRef
43.
Poy MN, Hausser J, Trajkovski M, Braun M, Collins S, Rorsman P, et al. miR-375 maintains normal pancreatic alpha- and beta-cell mass. Proc Natl Acad Sci USA. 2009;106:5813–8.
44.
Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 2004;432:226–30.PubMedCrossRef
45.
Avnit-Sagi T, Kantorovich L, Kredo-Russo S, Hornstein E, Walker MD. The promoter of the pri-miR-375 gene directs expression selectively to the endocrine pancreas. PloS One. 2009;4:e5033.PubMedCrossRef
46.
Simion A, Laudadio I, Prevot PP, Raynaud P, Lemaigre FP, Jacquemin P. MiR-495 and miR-218 regulate the expression of the Onecut transcription factors HNF-6 and OC-2. Biochem Biophys Res Commun. 2010;391:293–8.PubMedCrossRef
47.
Roggli E, Gattesco S, Caille D, Briet C, Boitard C, Meda P, et al. Changes in microRNA expression contribute to pancreatic beta-cell dysfunction in prediabetic NOD mice. Diabetes. 2012;61:1742–51.PubMedCrossRef
48.
•• Moran I, Akerman I, van de Bunt M, et al. Human beta cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab. 2012;16:435–48. This study integrated sequence-based transcriptome and chromatin maps of human islets and β cells to define a new class of islet genes: lncRNA that may impact diabetes pathophysiology. PubMedCrossRef
49.
Noonan EJ, Place RF, Pookot D, Basak S, Whitson JM, Hirata H, et al. miR-449a targets HDAC-1 and induces growth arrest in prostate cancer. Oncogene. 2009;28:1714–24.PubMedCrossRef
50.
Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nature Genet. 2006;38:228–33.PubMedCrossRef
51.
Zaret KS, Grompe M. Generation and regeneration of cells of the liver and pancreas. Science. 2008;322:1490–4.PubMedCrossRef
52.
Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotech. 2008;26:443–52.CrossRef
53.
Zhou Q, Melton DA. Extreme makeover: converting one cell into another. Cell Stem Cell. 2008;3:382–8.PubMedCrossRef
Metadata
Title
Epigenetic Regulation of Pancreatic Islets
Author
Cecile Haumaitre
Publication date
01-10-2013
Publisher
Springer US
Published in
Current Diabetes Reports / Issue 5/2013
Print ISSN: 1534-4827
Electronic ISSN: 1539-0829
DOI
https://doi.org/10.1007/s11892-013-0403-y

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Current Diabetes Reports 5/2013 Go to the issue

Transplantation (A Pileggi, Section Editor)

Biologic Agents in Islet Transplantation

Treatment of Type 1 Diabetes (JR Unger, Section Editor)

Continuous Glucose Monitoring: Current Use and Future Directions

Pathogenesis of Type 1 Diabetes (D Dabelea, Section Editor)

Is Autoimmunity or Insulin Resistance the Primary Driver of Type 1 Diabetes?

Pathogenesis of Type 1 Diabetes (D Dabelea, Section Editor)

Candidate Genes Expressed in Human Islets and Their Role in the Pathogenesis of Type 1 Diabetes

Pathogenesis of Type 1 Diabetes (D Dabelea, Section Editor)

Human Intestinal Microbiota and Type 1 Diabetes

Transplantation (A Pileggi, Section Editor)

Use of Glucagon-Like Peptide-1 Agonists to Improve Islet Graft Performance
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