Adrian Bird

Buchanan Chair of Genetics

Adrian Bird has held the Buchanan Chair of Genetics at the University of Edinburgh since 1990. He graduated in Biochemistry from the University of Sussex and obtained his PhD at Edinburgh University. Following postdoctoral experience at the Universities of Yale and Zurich, he joined the Medical Research Council’s Mammalian Genome Unit in Edinburgh. In 1987 he moved to Vienna to become a Senior Scientist at the Institute for Molecular Pathology. Following his return to Edinburgh he was Director of the Wellcome Centre for Cell biology (1999-2011), a governor of the Wellcome Trust and subsequently a trustee of Cancer Research UK. Awards include the Gairdner International Award, the BBVA Frontiers of Knowledge Award and the Shaw Prize. Adrian Bird’s research focuses on the basic biology of DNA methylation and other epigenetic processes. He identified CpG islands as gene markers in the vertebrate genome and discovered proteins that read the DNA methylation signal to influence chromatin structure. Mutations in one of these proteins, MeCP2, cause the severe neurological disorder Rett Syndrome. In 2007 Dr Bird’s laboratory established a mouse model of Rett Syndrome and showed that the resulting severe neurological phenotype is reversible, raising the possibility that the disorder in humans can be cured. He is a Fellow of the Royal Societies of Edinburgh and London, a member of the US National Academy of Sciences and was awarded a Knighthood in 2014.

Lab members

Beatrice Alexander-Howden, Grace Alston, Kashyap Chhatbar, John Connelly,Laura Fitzpatrick, Sarah Giuliani, Jacky Guy, Matthew Lyst, Nadina Skourti-Stathaki, Jim Selfridge,Verdiana Steccanella, Christine Struthers, Katie Paton, Raphael Pantier

A simple overview of research in the Bird lab - Research in a Nutshell Videos

MeCP2 and Rett syndrome

The chromosomal protein MeCP2 was discovered in 1992 while we were searching for potential “readers” of DNA methylation. Since the discovery by the Zoghbi laboratory that mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome, the protein has received much greater attention. We originally proposed that a primary role of MeCP2 is to recruit gene silencing machinery (known as a corepressor) to sites of DNA methylation. Accordingly, the great majority of point mutations that cause Rett syndrome inactivate either the DNA binding domain or the corepressor recruitment domain. In 2017, we showed that these two domains alone, which amount to only about one third of the wholeprotein, can fulfil key functions of the native protein. We also showed that the few Rett syndrome mutations that fall outside these key domains do not affect previously unidentified functional domains, but instead drastically reduce the abundance of MeCP2. These data support the idea that MeCP2 mediates the inhibitory effect of DNA methylation on gene expression. In agreement with this notion, absence of MeCP2 causes genes to be up-regulated in proportion to their local DNA methylation density.

MeCP2 dampens average levels of gene expression, but does not switch genes off. Also, its modulatory effect on the expression of any particular gene is not predicted by methylation density alone, as other regulatory mechanisms are involved and may dominate. To get at the underlying mechanism of transcriptional inhibition we adopted a multidisciplinary approach that utilised computational modelling (in collaboration with Dr Bartlomiej Waclaw of the School of Physics and Astronomy in Edinburgh). Using human neurons in culture as an experimental system, we constructed multiple cell lines that differed only by their widely divergent levels of MeCP2 expression. By mapping in detail protein binding, DNA methylation and gene expression, we were able to quantify important parameters. This information was then used to compare the expression of all genes with predictions of various theoretical models. While several models could be rejected, one proposing that MeCP2 slows transcriptional elongation through the bodies of genes was compatible with the data. We consider that this approach, whereby computational biology informs the way in which experimental data is collected and evaluated, may become increasingly important as a route to mechanistic understanding.

While MeCP2 modulates gene expression in response to DNA methylation, we found that a different nuclear protein, SALL4, inhibits differentiation of stem cells by reading the base composition of DNA. Regions of the genome that are rich in adenine and thymine bases attract SALL4, which brings with it a specific gene silencing complex causing down-regulation of genes locally. Our unpublished work suggests that this protein, like MeCP2, optimises gene expression patterns by interpreting the characteristic properties of the surrounding DNA.

Selected publications:

Bird, A. (2020). The Selfishness of Law-Abiding Genes. Trends in Genetics: TIG, 36(1), 8–13.

Cholewa-Waclaw, J., Shah, R., Webb, S., Chhatbar, K., Ramsahoye, B., Pusch, O., Yu, M., Greulich, P., Waclaw, B. and Bird, A.P. (2019).
Quantitative modelling predicts the impact of DNA methylation on RNA polymerase II traffic. Proc. Natl. Acad. Sci., 4(30), 201903549–15000.

Tillotson, R., & Bird, A. (2019). The Molecular Basis of MeCP2 Function in the Brain. Journal of Molecular Biology.

Creation of human cultured neurons expressing different levels of MeCP2.
A. Engineering of neuronal progenitor cells by disrupting, inhibiting or over-expressing the MECP2 gene.

B. Molecules of MeCP2 protein per neuronal nucleus after 9 days of differentiation.

C. Staining of 9 day differentiated neurons with no MeCP2 (KO), reduced MeCP2 (KD) or over-expressed MeCP2 (OE).
Data from Cholewa-Waclaw et al, 2019.