Integrative Analysis of Epigenomics and Expression data in an Immune Cell Proliferation System data in an Immune Cell Proliferation System Esteban Ballestar Esteban Ballestar Chromatin and Disease Group Chromatin and Disease Group Cancer Epigenetics and Biology Programme (PEBC) Bellvitge Medical Research Institute (IDIBELL) Barcelona Spain Barcelona, Spain [email protected]P P E E BC BC P P E E BC BC COST‐STATEGRA Workshop
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Integrative Analysis of Epigenomics and miRNA data in Immune System Models
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Integrative Analysis of Epigenomics and Expression data in an Immune Cell Proliferation Systemdata in an Immune Cell Proliferation System
Esteban BallestarEsteban Ballestar
Chromatin and Disease GroupChromatin and Disease GroupCancer Epigenetics and Biology Programme (PEBC)
Bellvitge Medical Research Institute (IDIBELL)Barcelona SpainBarcelona, Spain
DNA methylation changes in different models of immunedisease‐related disease: predominance of DNAh th l tihypomethylation
• ICF syndrome is a rare autosomal recessive disease characterized by a variableimmunodeficiency, mild facial anomalies, and centromeric decondensation—chromosomal instability involving chromosomes 1, 9, and 16, (1, 2). Hypomethylation ofthe satellite 2 and satellite 3 regions of chromosomes 1, 9, and 16 (3).
• Autoimmune diseases are characterized by the breakdown of immune tolerance tospecific self‐antigens. Two basic types: systemic (systemic lupus erythematosus,rheumatoid arthritis and psoriasis) and organ‐specific (Sjögren’s syndrome, type 1diabetes and multiple sclerosis). Analysis of different lymphocyte subsets have revealed apredominance of DNA hypomethylation/overexpression in key genes for immunefunction.
ICF syndrome: mutations in DNMT3b and hypomethylation
PNAS 96, 14412–14417 (1999)
Decrease of DNA methylation level of 42%, profound changes occurring ininactive heterochromatic regions, satellite repeats and transposons.Transcriptional active loci and ribosomal RNA repeats escape globalhypomethylation. Despite a genome‐wide loss of DNA methylation theepigenetic landscape and crucial regulatory structures are conserved.[Heyn et al (2012) Epigenetics]
Genetic Elements Hypomethylated in autoimmune diseases
Ballestar (2011) Nat. Rev. Rheumatol
MZ twins discordant for autoimmune diseases to investigate the role of DNA methylation in pathogenesis
Collection of MZ twins discordant for several AI diseases: SLE, RA, DMPBMC
Selected genes fall into various classes:tumor suppressor genes oncogenes genes involved in DNA repair cell cycle control differentiationdifferentiation apoptosis X‐linked imprinted genes
A set of genes display DNA hypomethylation in SLE with respect to healthy twins
• Transformation of resting B cells into proliferating lymphoblasts involveshypomethylation of around 250 genes. No hypermethylation is detected.
• A significant group of those 250 hypomethylated genes are already highly expressed inB cells, are bound by NFkB RELA and REL and other B cell specific transcription factorsand their expression levels do not change during this process.
• Hypomethylation does not appear to occur through an active process and it is likelythat is associated with the inefficient maintenance of DNA methylation at active regions(it does not occur at repetitive heterochromatic regions)(it does not occur at repetitive heterochromatic regions)
• Demethylation may contribute to the efficiency of the process by further enhancinggene upregulation of certain genesgene upregulation of certain genes
Chromatin and Disease Group, IDIBELL, Barcelona SpainLaura CiudadHenar HernandoVirginia RodríguezRoser Vento
Environmental Autoimmunity, NIEHS, NIH, BethesdaTerry O’HanlonLisa G. RiderFred Miller
Lorenzo de la RicaJosé UrquizaLluís PonsJavier Rodríguez‐Ubreva
Computational Medicine Unit, Karolinska Institutet, Stokholm, Sweden
University of OklahomaAmr Sawalha (U Michigan)John Harley (CCHMC)
Computational Medicine Unit, Karolinska Institutet, Stokholm, SwedenDavid Gómez‐CabreroJesper Tegnér