Adrian Bird

Bea Alexander-Howden, Amanda MacCallum, Kashyap Chhatbar, Sara Giuliani, Jacky Guy, Matthew Lyst, Katie Paton, Christine Struthers, James Watson, Jenna Hare, and Stan Morris

The past decade has seen a transformation in our understanding of the genetic basis of human disease due to the impact of high throughput DNA sequencing. An avalanche of new data has identified hundreds of genes that, when mutated, cause diseases as diverse as intellectual disability and cancer. While we know something about the function of many of the genes identified this way, we remain ignorant about why their malfunction leads to specific pathological changes. Filling this knowledge gap will be essential if we are to treat these conditions rationally. When the proteins encoded by these disease genes are categorised according to their likely function, a surprisingly large fraction turn out to be nuclear proteins involved in controlling gene expression via their effects on chromatin structure. Our research studies a small subset of these proteins to better understand how they might control where and when genes are expressed. By understanding the molecular mechanisms by which proteins of this type establish and maintain cell fate, we hope to illuminate the origins of specific human diseases.

We adopt a broad range of experimental and theoretical approaches, including genetics, cell biology and biochemistry. This breadth – from molecular to organismal levels – forces us to see biomedical issues from more than one perspective and keeps our research responsive. We benefit from being embedded within Centre for Cell Biology, which houses research groups studying the molecular basis fundamental cellular process and boasts state-of-the-art facilities. In addition, we are intimately involved in the Simons Initiative for the Developing Brain which investigates autism at diverse levels, including molecules, cells, circuits and behaviour. The broad range of expertise in biology, medicine and other sciences, plus an open culture of collaboration makes the University of Edinburgh, an ideal setting for our work.

Our research pursues three broad projects:

1. At the molecular level, we ask how the chromatin protein MeCP2 contributes to brain function? How do mutations in MeCP2 cause Rett syndrome? Can we devise genetic therapies that will markedly reduce Rett syndrome symptom severity?
2. MeCP2 recruits NCoR, a multi-protein corepressor complex that contains a histone deacetylase and inhibits transcription when brought close to gene. We have identified a variant of the NCoR complex called SET3 which contains two additional proteins: ANKRD11 and SETD5, both of which are within the top ten most frequently mutated proteins causing developmental delay/intellectual disability in humans. We ask: what is the function of SET3 and how does its absence lead to these syndromes?
3. The human genome comprises domains of relatively homogeneous base composition (A/T versus G/C) that are on average either AT-rich and gene poor, or AT-poor and gene-rich. We hypothesised that base composition can be read by proteins that recognise strings of A/T sequence motifs to influence gene expression. A screen for such proteins revealed SALL4 and we have shown that this protein indeed regulates chromatin structure and gene expression according to DNA base composition. We ask how this protein works at the molecular level and how it is involved in stabilizing the stem cell state.

Bird, A. (2025). Cohesin as an essential disruptor of chromosome organization.  Mol Cell 85, 1054-1057. https://doi.org/10.1016/j.molcel.2025.01.010

Pantier, R., Brown, M., Han, S., Paton, K., Meek, S., Montavon, T., Shukeir, N., McHugh, T., Kelly, D.A., Hochepied, T., et al. (2024). MeCP2 binds to methylated DNA independently of phase separation and heterochromatin organisation. Nat Commun 15, 3880. https://doi.org/10.1038/s41467-024-47395-1.

Bird, A. (2024). Transgenerational epigenetic inheritance: a critical perspective. Frontiers in Epigenetics and Epigenomics http://dx.doi.org/10.3389/freae.2024.1434253.

Tillotson, R., Cholewa-Waclaw, J., Chhatbar, K., Connelly, J.C., Kirschner, S.A., Webb, S., Koerner, M.V., Selfridge, J., Kelly, D.A., De Sousa, D., et al. (2021). Neuronal non-CG methylation is an essential target for MeCP2 function. Mol Cell 81, 1260-1275 e1212. 10.1016/j.molcel.2021.01.011.

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., et al. (2021). SALL4 controls cell fate in response to DNA base composition. Mol Cell 81, 845-858 e848. 10.1016/j.molcel.2020.11.046.