An ENU screen in the mouse reveals the role of epigenetics in disease phenotypes
Epigenetic modifications to the genome are crucial for the correct regulation of transcription, are mitotically stable, and are essential for the differentiation of cell lineages, and the fidelity of cell type within lineages. Proteins involved in the establishment and maintenance of the epigenetic state include DNA methyltransferases (e.g. Dnmt1, Dnmt3a), histone modification enzymes (e.g. histone deacetylases and methylases), and chromatin remodelling proteins (e.g. SWI/SNF proteins). Some human diseases have been linked to mutations in genes that encode epigenetic modifiers. For example, Rhett syndrome, a disease associated with early-onset mental retardation, results from mutation in the mehtyl-binding protein MeCP2, and mutation in ATRX, a SNF-2-like chromatin remodelling protein are associated with mental retardation, α-thalassaemia and other developmental abnormalities
We have used a sensitised screen to identify mouse mutants displaying altered epigentic pocesses. Our screen relies on a red blood cell specific GFP transgene that is expressed in approximately 60% of erythrocytes in the FVB inbred mouse strain. This variegation correlates with DNA methylation at the transgene. So far we have identified fifteen mutant lines from our screen. Linkage analysis reveals that the mutations map to unique chromsomal locations. We have identified the genes underlying five of the mutation, SmchD1, Dnmt1, Snf2h, Foxo3a and WSTF.
WSTF is a gene in the Williams-Beuren Syndrome (WBS) linked region in humans. WBs patients have characteristic facial features, mental retardation, short stature and other developmental abnormalities. There are approximately 28 genes in the WBS critical region, and there is debate about the role that each gene plays in the disease phenotype (Donnai et al, 2005). Our WSTF mutatn homozygous mice show reduced survival, are significantly smaller than littermates and have an abnormal face reminiscent of that seen in WBS. It seems likely taht WSTF plays a role in the phenotype of WBS in humans.