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FUGE-Funksjonell genomforskn.i Norg

Epigenetic surveying in immune-mediated diseases. A twin study.

Tildelt: kr 8,0 mill.

Background: Genetically complex diseases, e.g. immune-mediated diseases are caused by a complex interplay between susceptibility genes and environment. The impact of environmental factors is clearly demonstrated in twin studies showing concordance rates i n MZ twins well below 100%. One impact of environmental factors may be through introduction of genome modifications that generate epigenetic variation and ultimately lead to variation in gene expression. Because identical twins are perfectly correlated fo r background genetic and key environmental factors, the disease- or exposure-discordant MZ twin design is a particularly powerful tool for discovering epigenetic variation. Aim: To test the hypothesis that epigenetic variation contributes to disease susce ptibility in immune mediated diseases, in particular asthma and psoriasis. We aim to develop novel methods for whole genome epigenetic surveying (WGES), based on novel ultra high-throughput sequencing (UHTS) technology. Materials: We will study MZ twins d iscordant for these diseases. Epigenetic variation is tissue specific, and in immune mediated diseases lymphocytes are known to be important players and are relevant to study. Methods: Blood will be drawn, and relevant subsets of lymphocytes will be isola ted for DNA/RNA extraction. CD4+ lymphocyte cultures will be established. We will perform ChIP experiments and UHTS of bisulfite converted DNA to determine chromatin modifications and methylation variable regions (MVRs). We will analyse within pair epigen etic differences in discordant twins to determine if any MVRs are disease associated. Confirmatory analysis will be conducted using RT-PCR to determine effect on gene expression and in case control materials to determine effect on disease susceptibility. Importance: The project can elucidate critical pathways underlying the development of these two important diseases. It will also lead to development of new methods for WGES that can be used in further studies.

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FUGE-Funksjonell genomforskn.i Norg