title: Transcriptome analysis of epigenetically modulated genome indicates signature genes in manifestation of type 1 diabetes and its prevention in NOD mice.
abstract: Classic genetic studies implicated several genes including immune response genes in the risk of developing type 1 diabetes in humans. However, recent evidence including discordant diabetes incidence among monozygotic twins suggested a role for epigenetics in disease manifestation. NOD mice spontaneously develop type 1 diabetes like humans and serve as an excellent model system to study the mechanisms of type 1 diabetes as well as the efficacy of maneuvers to manipulate the disease. Using this preclinical model, we have recently demonstrated that pharmacological inhibition of histone deacetylases can lead to histone hyperacetylation, selective up-regulation of interferon-γ and its transactivator Tbx21/Tbet, and amelioration of autoimmune diabetes. In the current study, we show that chromatin remodeling can render splenocytes incapable of transferring diabetes into immunodeficient NOD.scid mice. To elucidate the underlying mechanisms of drug-mediated protection against type 1 diabetes, we performed global gene expression profiling of splenocytes using high throughput microarray technology. This unbiased transcriptome analysis unraveled the exaggerated expression of a novel set of closely related inflammatory genes in splenocytes of acutely diabetic mice and their repression in mice cured of diabetes by chromatin remodeling. Analysis of gene expression by qRT-PCR using RNA derived from spleens and pancreata of cured mice validated the suppression of most of these genes, indicating an inverse correlation between the high levels of these inflammatory genes and protection against diabetes in NOD mice. In addition, higher-level expression of genes involved in insulin sensitivity, erythropoiesis, hemangioblast generation, and cellular redox control was evident in spleens of cured mice, indicating their possible contribution to protection against type 1 diabetes. Taken together, these results are consistent with the involvement of epistatic mechanisms in the manifestation of autoimmune diabetes and further indicate the utility of chromatin remodeling in curing this complex autoimmune disorder.
authors: Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA. anue2468@uic.edu
authors: Sundararajan
authors: S
authors: Jayaraman
authors: Akshay
authors: A
authors: Patel
authors: Arathi
authors: A
authors: Jayaraman
authors: Vasu
authors: V
authors: Patel
authors: Mark
authors: M
authors: Holterman
authors: Bellur
authors: B
authors: Prabhakar
mesh_terms: D000818:Animals; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015536:Down-Regulation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics; D007249:Inflammation / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D013601:T-Lymphocytes / Q000276:immunology
references: Nat Protoc. 2009;4(1):44-57
references: 19131956
references: Eur J Immunol. 2009 Jan;39(1):216-24
references: 19130584
references: Epigenetics. 2010 May 16;5(4):267-72
references: 20364108
references: Adv Exp Med Biol. 2011;711:162-77
references: 21627049
references: J Immunol. 2005 Dec 1;175(11):7738-45
references: 16301684
references: Circ Res. 2010 Oct 29;107(9):1058-70
references: 21030723
references: Horm Res Paediatr. 2011;76 Suppl 1:57-64
references: 21778751
references: Jikken Dobutsu. 1980 Jan;29(1):1-13
references: 6995140
references: Nature. 2002 May 2;417(6884):91-4
references: 12018205
references: J Biomed Biotechnol. 2011;2011:371832
references: 21151613
references: Epigenomics. 2011 Oct;3(5):639-48
references: 22126251
references: J Diabetes. 2010 Dec;2(4):267-74
references: 20923497
references: Diabetes. 1993 Jan;42(1):44-55
references: 8093606
references: Immunol Cell Biol. 2011 Jul;89(5):640-9
references: 21321581
references: Dev Comp Immunol. 1979 Winter;3(1):67-75
references: 437238
references: Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10107-12
references: 18632574
references: Antioxid Redox Signal. 2009 Apr;11(4):777-90
references: 18828708
references: Eur J Immunol. 1991 Sep;21(9):2051-5
references: 1889456
references: Circ Res. 2012 Apr 13;110(8):1039-41
references: 22499895
references: Genomics. 2001 Aug;76(1-3):2-4
references: 11549310
references: Biochim Biophys Acta. 1975 Sep 22;403(1):161-79
references: 240426
references: Mediators Inflamm. 2010;2010:610479
references: 20169173
references: Handb Exp Pharmacol. 2011;206:103-23
references: 21879448
references: Biochim Biophys Acta. 2010 Oct-Dec;1799(10-12):717-25
references: 20594930
references: Am J Pathol. 2006 Dec;169(6):2137-47
references: 17148676
references: J Immunol. 2004 Mar 1;172(5):2731-8
references: 14978070
references: J Exp Med. 1997 Jul 21;186(2):299-306
references: 9221759
references: Diabetes. 2007 Feb;56(2):424-30
references: 17259387
references: Blood. 2007 Nov 15;110(10):3601-9
references: 17675553
references: Immunity. 2010 Apr 23;32(4):457-67
references: 20412756
references: Dev Comp Immunol. 1977 Apr;1(2):133-43
references: 76578
references: Clin Immunol. 2008 Nov;129(2):195-201
references: 18801706
references: J Immunol. 2000 Apr 1;164(7):3919-23
references: 10725755
references: J Clin Endocrinol Metab. 2008 Feb;93(2):578-83
references: 18029454
references: Proc Natl Acad Sci U S A. 1969 Dec;64(4):1176-80
references: 5271746
references: Diabetes. 2004 Feb;53(2):366-75
references: 14747287
references: Expert Opin Ther Targets. 2011 Mar;15(3):237-51
references: 21208136
references: J Autoimmun. 2002 Nov;19(3):129-37
references: 12419283
references: J Immunol. 2010 Mar 15;184(6):3008-15
references: 20164427
references: Physiol Genomics. 2005 Apr 14;21(2):201-11
references: 15671250
references: J Immunol. 2008 Jan 15;180(2):1071-9
references: 18178847
references: Diabetes. 2003 Apr;52(4):1052-5
references: 12663480
references: Curr Med Chem. 2004 Jun;11(12):1629-43
references: 15180568
references: J Autoimmun. 2004 Dec;23(4):311-21
references: 15571925
references: Cell Cycle. 2007 Jun 15;6(12):1419-25
references: 17592253
references: Trends Mol Med. 2008 Jun;14(6):268-75
references: 18482868
references: Adv Immunol. 2008;100:151-75
references: 19111166
references: BMC Med Genomics. 2009 Oct 02;2:63
references: 19799787
references: Genome Res. 2002 Feb;12(2):232-43
references: 11827943
references: J Clin Invest. 2009 Mar;119(3):565-72
references: 19188681
references: Pharmacol Rev. 2010 Dec;62(4):726-59
references: 21079042
references: J Immunol. 2001 Jan 15;166(2):1352-9
references: 11145720
references: Genome Biol. 2008;9(6):R99
references: 18554416