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

Kashyap Chhatbar, John Connelly, Laura Fitzpatrick, Sara Giuliani, Jacky Guy, Beatrice Alexander-Howden, Matthew Lyst, Baisakhi Mondal, Raphael Pantier, Katie Paton, Verdiana Steccanella, Christine Struthers

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

Understanding proteins that interpret the genome to stabilise cell states

Regulation of gene expression in eukaryotes is complex, but probably ultimately depends on proteins that recognise specific DNA sequences. Our recent work emphasises this relationship by showing an unexpected dependence of gene activity on proteins that recognise short, frequent base sequence motifs (Figure 1). This points to a broad-brush category of control whereby genes can be up- or down-regulated based on the DNA sequence properties of their genomic location. Our studies of this phenomenon have centred on two proteins that are implicated in human disease: MeCP2 and SALL4. 

MeCP2 contains a DNA binding domain that requires DNA methylation in either a CG or a CAC context. This protein is highly expressed in mature neurons and its deficiency causes the profound neurological disorder Rett syndrome. We showed previously that MeCP2 restrains gene expression by recruiting a corepressor to the genome. Recently, we questioned the importance of the unusual methyl-CAC target site, which is abundant only in neurons. To do this, we replaced the DNA binding domain of MeCP2 with one that can bind mCG but not mCAC. Mice dependent on this protein had Rett syndrome-like phenotypes, indicating that mCAC binding is essential for the function of MeCP2. These experiments also allowed us to identify a subset of de-regulated genes that are mis-expressed in other neurological disorders and may be implicated in Rett syndrome. Future work will explore this possibility further. 

The second protein under study is SALL4, a multi-zinc-finger protein that plays an important role in development and disease. For example, SALL4 is highly expressed in many cancers with poor prognosis. We speculated that it might interpret DNA base composition by recognising AT-rich DNA and, in agreement with this notion, found that a zinc finger cluster specifically targets short A/T-rich motifs in the genome and recruits a partner corepressor. In embryonic stem cells, this represses a set of AT-rich differentiation genes, thereby prolonging the pluripotent state. Prevention of AT-binding activates these genes, leading to precocious differentiation. It has been recognised for decades that the mammalian genome is organised in long domains with distinct, evolutionarily-conserved base compositions. Our SALL4 study provides the first evidence that base composition can be read as a biological signal to regulate gene expression.

Despite major differences between MeCP2 and SALL4 in protein sequence, pattern of expression and the physiological consequences of mutation, they share striking similarities. Both recognise short DNA sequence motifs that are frequent in the genome and both recruit corepressor complexes leading to widespread modulation of gene expression. Future work will seek a comprehensive mechanistic picture of the ways in which mechanisms of this kind help to define and stabilise cell states, and how defects in this system lead to disease.

Selected publications:

Tillotson, R., Cholewa-Waclaw, J., Chhatbar, K., Connelly, J., Kirschner, S.A., Webb, S., Koerner, M.V., Selfridge, J., Kelly, D., De Sousa, D., Brown, K., Lyst, M.J., Kriaucionis, S. and Bird, A. (2021). Neuronal non-CG methylation is an essential target for MeCP2 function. Mol Cell 81, 1-16.  PMID: 33561390

Pantier, R., Chhatbar, K., Quante, T., Skourti-Stathaki, K., Cholewa-Waclaw, J., Alston, G., Alexander-Howden, B., Lee, H.Y., Cook, A.G., Spruijt, C.G., Vermeulen, M., Selfridge, J. and Bird, A. (2020). SALL4 controls cell fate in response to DNA base composition. Mol Cell 81(4): 1-16 PMID: 33406384

Bird, A. (2020). The Selfishness of Law-Abiding Genes. Trends Genet 36, 8-13. 10.1016/j.tig.2019.10.002  PMID: 31662191

Similarities and differences between SALL4 and MeCP2 function. Both mediate the effects of short, frequent DNA sequence motifs on gene expression by recruiting corepressors containing histone deacetylases (HDACs). However, they recognise different base sequences (methylcytosine-containing versus AT-rich) and recruit different corepressor complexes (NCoR versus NuRD) associated with distinct HDACs (HDAC3 versus HDAC1/2).