title: Lymphocytes from patients with type 1 diabetes display a distinct profile of chromatin histone H3 lysine 9 dimethylation: an epigenetic study in diabetes.
abstract: OBJECTIVE
  The complexity of interactions between genes and the environment is a major challenge for type 1 diabetes studies. Nuclear chromatin is the interface between genetics and environment and the principal carrier of epigenetic information. Because histone tail modifications in chromatin are linked to gene transcription, we hypothesized that histone methylation patterns in cells from type 1 diabetic patients can provide novel epigenetic insights into type 1 diabetes and its complications.
  
  
  METHODS
  We used chromatin immunoprecipitation (ChIP) linked to microarray (ChIP-chip) approach to compare genome-wide histone H3 lysine 9 dimethylation (H3K9me2) patterns in blood lymphocytes and monocytes from type 1 diabetic patients versus healthy control subjects. Bioinformatics evaluation of methylated candidates was performed by Ingenuity Pathway Analysis (IPA) tools.
  
  
  RESULTS
  A subset of genes in the type 1 diabetic cohort showed significant increase in H3K9me2 in lymphocytes but not in monocytes. CLTA4, a type 1 diabetes susceptibility gene, was one of the candidates displaying increased promoter H3K9me2 in type 1 diabetes. IPA identified two high-scoring networks that encompassed genes showing altered H3K9me2. Many of them were associated with autoimmune and inflammation-related pathways, such as transforming growth factor-beta, nuclear factor-kappaB, p38 mitogen-activated protein kinase, toll-like receptor, and interleukin-6. IPA also revealed biological relationships between these networks and known type 1 diabetes candidate genes.
  
  
  CONCLUSIONS
  The concerted and synergistic alteration of histone methylation within the identified network in lymphocytes might have an effect on the etiology of type 1 diabetes and its complications. These studies provide evidence of a novel association between type 1 diabetes and altered histone methylation of key genes that are components of type 1 diabetes-related biological pathways and also a new understanding of the pathology of type 1 diabetes.
authors.affiliation: Department of Diabetes, Beckman Research Institute of City of Hope, Duarte, CA, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Miao
authors.forename: David D
authors.initials: DD
authors.lastname: Smith
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Zhang
authors.forename: Andrew
authors.initials: A
authors.lastname: Min
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000235:genetics*; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D004777:Environment; D044127:Epigenesis, Genetic / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006657:Histones / Q000235:genetics*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism*; D008239:Lysine / Q000031:analogs & derivatives* / Q000235:genetics; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D055815:Young Adult
chemical_list: D002843:Chromatin; D006657:Histones; C018926:epsilon N-dimethyllysine; D008239:Lysine
references.citation: J Biol Chem. 2007 May 4;282(18):13854-63
references.pmid: 17339327
references.citation: Genes Dev. 2002 Jul 15;16(14):1779-91
references.pmid: 12130538
references.citation: Nat Genet. 2005 Apr;37(4):391-400
references.pmid: 15765097
references.citation: J Immunol. 2008 Feb 15;180(4):2264-9
references.pmid: 18250434
references.citation: Cell. 2007 Jul 13;130(1):25-35
references.pmid: 17632054
references.citation: Nature. 2005 Sep 15;437(7057):436-9
references.pmid: 16079795
references.citation: Mol Cell. 2007 Aug 17;27(4):622-35
references.pmid: 17707233
references.citation: Nat Rev Genet. 2007 Apr;8(4):253-62
references.pmid: 17363974
references.citation: JAMA. 2002 May 15;287(19):2563-9
references.pmid: 12020338
references.citation: Nature. 2000 Jan 6;403(6765):41-5
references.pmid: 10638745
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references.pmid: 11309499
references.citation: Genes Dev. 2004 Jun 1;18(11):1263-71
references.pmid: 15175259
references.citation: Cell. 2005 Jan 28;120(2):169-81
references.pmid: 15680324
references.citation: Science. 2001 Aug 10;293(5532):1074-80
references.pmid: 11498575
references.citation: Nature. 1980 Oct 9;287(5782):509-16
references.pmid: 7422003
references.citation: Cell. 2006 May 5;125(3):483-95
references.pmid: 16603237
references.citation: JAMA. 2003 Oct 22;290(16):2159-67
references.pmid: 14570951
references.citation: J Biol Chem. 2001 Jul 6;276(27):25309-17
references.pmid: 11316813
references.citation: Nature. 2001 Nov 15;414(6861):277-83
references.pmid: 11713521
references.citation: Diabet Med. 2007 Jun;24(6):582-6
references.pmid: 17490424
references.citation: Mol Cell. 2003 Dec;12(6):1591-8
references.pmid: 14690610
references.citation: Science. 2000 Dec 22;290(5500):2306-9
references.pmid: 11125145
references.citation: Mol Cell Biol. 2005 Jun;25(11):4650-61
references.pmid: 15899867
references.citation: Annu Rev Immunol. 2002;20:29-53
references.pmid: 11861596
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9047-52
references.pmid: 18579779
references.citation: Trends Genet. 2003 Nov;19(11):629-39
references.pmid: 14585615
references.citation: Nat Genet. 2005 Oct;37(10):1090-7
references.pmid: 16155569
references.citation: Trends Genet. 2004 Aug;20(8):350-8
references.pmid: 15262407
references.citation: Nature. 1994 Sep 8;371(6493):130-6
references.pmid: 8072542
references.citation: Genome Biol. 2004;5(10):R80
references.pmid: 15461798
references.citation: Annu Rev Biochem. 2006;75:243-69
references.pmid: 16756492
references.citation: Nat Cell Biol. 2007 Mar;9(3):347-53
references.pmid: 17277772
references.citation: Biometrics. 2007 Sep;63(3):787-96
references.pmid: 17825010
references.citation: Nature. 2007 May 24;447(7143):433-40
references.pmid: 17522677
references.citation: J Immunol. 2008 Feb 1;180(3):1929-37
references.pmid: 18209091
references.citation: Nat Genet. 2007 Jul;39(7):857-64
references.pmid: 17554260
references.citation: Mol Cell Biol. 2006 Sep;26(18):6890-901
references.pmid: 16943430
references.citation: J Biol Chem. 2004 Apr 23;279(17):18091-7
references.pmid: 14976218
references.citation: Diabetes. 2003 May;52(5):1300-5
references.pmid: 12716770
references.citation: Nature. 2005 Jun 30;435(7046):1262-6
references.pmid: 15988529
references.citation: Mol Cell. 2003 Dec;12(6):1577-89
references.pmid: 14690609