Research Interests



Our research group is interested in the structure and function of the mammalian genome, and in particular the role of DNA methylation. It has been known for some time that the methylation of cytosine near a gene can repress transcription. We have identified proteins that mediate repression by binding to methylated DNA, and are studying their biology. The founding member of the family is MeCP2, which represses transcription of methylated genes by recruitment of a corepressor complex that contains histone deacetylases. The MECP2 gene is clinically important as mutations within it are the primary cause of Rett Syndrome, a severe inherited neurological disorder that affects girls. We are creating a mouse model of Rett Syndrome by targetted mutation of MeCP2. Similar biochemical and genetic methods are being used to study the other methyl-CpG binding repressors. MBD4, however, is a member of the protein family that does not appear to be involved in transcriptional silencing. Instead we found that it behaves as a DNA repair protein that can catalyse the removal of mismatched bases from DNA. The properties of MBD4 suggest that its primary role may be to initiate repair of deaminated 5-methylcytosine residues, which are a major source mutations that can human genetic disease. The laboratory also has an interest in the origin of "CpG islands", which are regions that lack DNA methylation surrounding the promoters of most human genes. What is it that keeps CpG islands methylation-free of in an otherwise heavily methylated genome? Our research indicates that promoter activity is crucial. The evolution of gene number is also an active area of our research.