DNA METHYLOME STUDY IN TYPE 1 DIABETES

Summary

Principal Investigator: ART PETRONIS
Abstract: Project Summary Epigenetics refers to the heritable, but reversible, regulation of genes that is controlled by chemical attachments to DNA and chromosome proteins. Inherited and acquired epigenetic misregulation is consistent with numerous disease features. In type 1 diabetes (T1D), epigenetic mechanisms can explain why 35% of monozygotic twins exhibit differential susceptibility to T1D, i.e. only one twin is affected and his/her co-twin stays healthy despite their identical DNA sequences and similar environmental exposure. Differences in the incidence of T1D between males and females could also be of epigenetic origin. In a similar way, the observation that men with T1D are more likely to transmit the disease to their offspring than their female counterparts may be the result of epigenetic differences in the maternal genes vs. paternal genes. To date, however, few studies have investigated the role of epigenetic factors in T1D, and none have utilized an epigenome-wide approach. This project is dedicated to the comprehensive epigenomic analysis of T1D. More specifically, we will investigate DNA methylation, which is one of the key epigenetic mechanisms. The main goal of this project is to identify DNA methylation alterations, or epimutations, that cause or predispose individuals to T1D. Our first aim is to uncover DNA methylation changes that lead to misregulation of the insulin gene in the thymus. The rationale for this study is based on the observation that if there is not enough insulin in the thymus during embryogenesis, immune cells that produce antibodies against insulin will stay alive. Later in life, such cells may attack pancreatic cells that synthesize insulin, and this will result in T1D. We hypothesize that lack of insulin in the thymus is, to some extent, due to epigenetic misregulation of the insulin gene. Our effort will be dedicated to a detailed DNA methylation analysis of several million nucleotides that surround the insulin gene. The detected DNA methylation factors that account for low activity of the insulin gene will be tested in large samples of T1D patients and control individuals. Our second aim is to perform whole DNA methylome studies in peripheral blood samples from pairs of twins and non-twin siblings where only one of the twins or siblings is affected with T1D. To identify which epigenetic changes were inherited and which ones were acquired later in life, we will test germline samples of fathers who have children with T1D and are also affected with T1D themselves or have a family history of T1D. DNA methylation patterns will be investigated in over 1,000 DNA samples from individuals with T1D and their unaffected relatives. The project should help us understand the molecular basis of T1D. The identification of epigenetic disease markers would be of critical importance in the diagnostic, treatment, and prophylactic applications in T1D. PUBLIC HEALTH RELEVANCE: Project Narrative There is increasing theoretical and experimental evidence that epigenetic misregulation may be involved in the etiopathogenesis of type 1 diabetes (T1D). In this project, we plan to perform a very large scale epigenome study of T1D, which may uncover the molecular mechanisms by which genes become disregulated and predispose to T1D. This effort may have a major impact on our understanding of autoimmune mechanisms in T1D and lead to new strategies in diagnostics and treatment of the disease.
Funding Period: 2009-09-25 - 2012-08-31
more information: NIH RePORT

Top Publications

  1. pmc 5-hmC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary
    Tarang Khare
    The Krembil Family Epigenetics Laboratory, The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
    Nat Struct Mol Biol 19:1037-43. 2012
  2. ncbi DNA unmethylome profiling by covalent capture of CpG sites
    Edita Kriukiene
    Department of Biological DNA Modification, Institute of Biotechnology, Vilnius University, Vilnius LT 02241, Lithuania
    Nat Commun 4:2190. 2013
  3. ncbi Epigenetics as a unifying principle in the aetiology of complex traits and diseases
    Arturas Petronis
    The Krembil Family Epigenetics Laboratory, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada
    Nature 465:721-7. 2010
  4. pmc A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells
    Masoud Vedadi
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada
    Nat Chem Biol 7:566-74. 2011

Scientific Experts

  • ART PETRONIS
  • Edita Kriukiene
  • Tarang Khare
  • Sun Chong Wang
  • Viviane Labrie
  • Shraddha Pai
  • Carolyn Ptak
  • Saulius Klimasauskas
  • Karolis Koncevicius
  • Masoud Vedadi
  • Juozas Gordevicius
  • Daofeng Li
  • Audrone Lapinaite
  • Ting Wang
  • Giedre Urbanaviciute
  • Mamoru Tochigi
  • Raymond Tice
  • Solange Morera
  • Menghang Xia
  • Zita Liutkeviciute
  • Manuel Irimia
  • Rafal Kustra
  • Benjamin J Blencowe
  • Philipp Kapranov
  • Denise Belsham
  • Anaies Nazarians
  • Peixin Jia
  • Mrinal Pal
  • Albert H C Wong
  • Jacqueline L Norris
  • Dalia Barsyte-Lovejoy
  • Samantha G Pattenden
  • Peter J Brown
  • Stephen V Frye
  • Abdellah Allali-Hassani
  • Wolfram Tempel
  • Tim J Wigle
  • Ashutosh Tripathy
  • Cheryl H Arrowsmith
  • William P Janzen
  • Xi Ping Huang
  • Catherine D Simpson
  • James Ellis
  • Irene Chau
  • Peter A DiMaggio
  • Gregory A Wasney
  • Xin Chen
  • Aled Edwards
  • Sylvie Rival-Gervier
  • Aiping Dong
  • Thomas J Mangano
  • Bryan L Roth
  • Jian Jin
  • Dmitri B Kireev
  • Alena Siarheyeva
  • Feng Liu
  • Benjamin A Garcia

Detail Information

Publications4

  1. pmc 5-hmC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary
    Tarang Khare
    The Krembil Family Epigenetics Laboratory, The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
    Nat Struct Mol Biol 19:1037-43. 2012
    ..Moreover, in human frontal cortex, constitutive exons contained higher levels of 5-hmC relative to alternatively spliced exons. Our study suggests a new role for 5-hmC in RNA splicing and synaptic function in the brain...
  2. ncbi DNA unmethylome profiling by covalent capture of CpG sites
    Edita Kriukiene
    Department of Biological DNA Modification, Institute of Biotechnology, Vilnius University, Vilnius LT 02241, Lithuania
    Nat Commun 4:2190. 2013
    ....
  3. ncbi Epigenetics as a unifying principle in the aetiology of complex traits and diseases
    Arturas Petronis
    The Krembil Family Epigenetics Laboratory, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario M5T 1R8, Canada
    Nature 465:721-7. 2010
    ..Epigenetics can provide a new framework for the search of aetiological factors in complex traits and diseases...
  4. pmc A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells
    Masoud Vedadi
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada
    Nat Chem Biol 7:566-74. 2011
    ..In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation...