“Our work uses a broad range of technologies to answer questions about the role of DNA methylation in health and disease. At one extreme, we study animal models of the debilitating autism spectrum disorder Rett Syndrome to better understand the disease, while at the other, we collaborate with X-ray crystallographers to get at the atomic structure of proteins that read the DNA methylation signal. This breadth – from molecules to organisms - forces us to see biomedical issues at more than one level and keeps our research both exciting and cutting-edge. We benefit enormously from being embedded within the Wellcome Trust Centre for Cell Biology, which house 16 world-class research groups studying the basic biology of cells and boasts state-of-the-art facilities. The superb range of biological and medical expertise at Edinburgh University is also a major asset for us.”

Adrian Bird, Group Leader

The Bird Lab is part of the Wellcome Trust Centre for Cell Biology. The Centre for Cell Biology is one of nine UK-based Wellcome Trust Centres, three of which are in Scotland.

During the past decade, the genomic DNA sequence of humans and many other organisms has been determined with a high degree of accuracy, but profound questions remain about the influence of nucleotide sequence on genome function. Most genomic DNA does not encode protein, but it is increasingly clear that it can strongly influence gene activity. To better understand how genetic information is computed to create a cellular phenotype, functional annotation of the genome needs to be extended to include this non-coding majority of DNA. Our laboratory studies the dinucleotide sequence CpG, which is distributed genome-wide and has several properties expected of a genomic signalling module. In particular, it exists in three chemically modified forms – non-methylated, methylated and hydroxymethylated. CpG density varies widely, being most dense at so-called CpG islands, many of which exist in either a methylated or an unmethylated state. We know that dense methylation of a CpG island silences the associated gene whereas absence of methylation permits transcription. Nevertheless, the extent to which DNA methylation is involved in development, differentiation and disease is only just beginning to emerge. A major theme of our work is to understand ways in which the CpG module is read by proteins to generate biological outcomes. We study not only the distribution of methylated and non-methylated CpGs in the genome, but also proteins that bind differentially to either form. In general, methyl-CpG binding proteins recruit chromatin modifying enzymes to cause gene silencing, whereas CpG binding proteins, which have been relatively less studied, promote the formation of active chromatin marks. The methylated form of CpG is distributed at low density throughout the genome, but also occurs at high density when CpG islands become methylated. One of the best studied methyl-CpG binding proteins is MeCP2, which in neurons is almost as abundant as the histones. MeCP2-deficient children acquire serious neurological disorders, in particular the autism spectrum disorder Rett Syndrome. Due to its monogenic origin, Rett Syndrome has become one of the most experimentally accessible of the so-called “neuro-developmental disorders” and studies of MeCP2 offer a golden opportunity to understand its complex pathology at a molecular level. The availability of mouse models of Rett Syndrome has accelerated our understanding of this disorder. We recently used a model to demonstrate that Rett-like symptoms in mice can be readily reversed by restoration of a functional MeCP2 gene, even when the mouse has advanced neurological symptoms. This result has raised the prospect that Rett Syndrome itself might be curable and has stimulated the search for therapeutic approaches. Our work has focused on improving the molecular understanding of MeCP2 function in the brain, in the hope that this knowledge will contribute to this goal.