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Epigenetic regulation of gene expression: transgenic mouse model systems of variable expressivity in genetic disease

Objective



Epigenetic control of gene expression by DNA methylation and chromatin mechanisms plays a crucial role in normal development, genetic disease, and cancer. It is therefore important to identify genetic factors that control methylation and chromatin structure, as these factors are likely to contribute to cancer susceptibility and to predisposition and expression of many genetic diseases, and are likely to play an important role in multifactorial causes of disease. The centres that are involved in this proposed Epigenetics Network have previously developed transgenic model systems in the mouse that show variable transgene expression and repression associated with DNA methylation and chromatin compaction which is controlled by genotype-specific modifier genes in the genome. Here it is proposed to use three different transgenic systems as well as endogenous gene targets of epigenetic control, to genetically characterise and map modifier genes which are responsible for this variable expression and methylation. The genetic fine mapping of these modifier genes will eventually lead to their isolation by positional cloning. The developmental and lineage-specific action of modifier genes will be analyzed, and embryonic stem (ES) cells will be isolated that carry transgenic targets. This will eventually establish a test system for candidate modifier genes. The sequence targets of modifier action will be defined using the already established transgenic mouse strains. Endogenous target sequences of modifier action will be isolated using RDA (Representational Difference Analysis).

Mapping and characterisation of modifier genes will lead to a better understanding of the epigenetic mechanisms of gene regulation. Since these genes are likely to play a major role in multifactorial diseases that are characterised by variable expressivity, they are strong candidates for `risk alleles' in a number of genetic diseases and cancers. This research will therefore make an important future contribution to the molecular diagnosis, predictive testing and genetic counselling in a potentially large number of genetic disorders.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

THE BABRAHAM INSTITUTE
Address
Babraham Hall
CB2 4AT Cambridge
United Kingdom

Participants (3)

CENTRE HOSPITALIER UNIVERSITAIRE DE NANTES
France
Address
Boulevard Jean Monnet 30
44035 Nantes
Max-Planck-Gesellschaft zur Förderungder Wissenschaften e.V.
Germany
Address
73,Ihnestrasse
14195 Berlin
Universität Köln
Germany
Address
121,Weyertal
50931 Köln