Adrian Bird

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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.

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Understanding proteins that stabilise cell identity

MeCP2 is highly expressed in mature neurons and MeCP2-deficiency causes the profound neurological disorder Rett syndrome (RTT), in which neurons show morphological and electrophysiological defects. We previously showed that the mouse provides a convincing model of this disorder and found, remarkably, that the severe phenotypes are reversed if the protein is restored in adulthood. Thus, MeCP2 is dispensable for neurodevelopment, but essential for maintenance of the mature neuronal state.

We have made significant recent progress in elucidating the molecular mechanism underlying MeCP2 function. We showed previously that DNA binding by MeCP2 depends on 5-methycytosine in a mCG context. Work by others showed that mCA also bound MeCP2 and this was subsequently narrowed down by our demonstration that the trinucleotide mCAC is the overwhelmingly prefered non-CG DNA binding motif. Coincidentally, CAC is the preferred non-CG target for the DNA methyltransferase DNMT3A and is highly methylated in mature neurons. To determine the biological importance of mCAC binding, we replaced the MeCP2 DNA binding domain with that of the related protein MBD2. The MBD2 domain specifically binds mCG but does not detectably interact with mCAC in vitro or in vivo. The results showed that mice expressing only the domain-swap protein displayed Rett syndrome like phenotypes, indicating that mCAC is an essential MeCP2 target.

Comparative transcriptomics indicates that MeCP2 functions to restrain expression of large numbers of genes in a DNA methylation-dependent manner. Assuming that transcriptional disturbance leads to the neuronal dysfunction that underlies RTT, two extreme hypotheses are: 1) RTT is the aggregate outcome of slightly perturbed expression of very many genes; 2) RTT strongly depends on dysregulation of a few key genes. Our recent work highlights shared dysregulated genes in different mouse models with RTT-like phenotypes, allowing a test the second possibility. Specifically, mice expressing a chimaeric MeCP2 that is unable to bind mCAC and Mecp2-KO mice both up-regulate genes causally implicated in autism-related disorders, including AUTS2, CNTN4, MEF2C, GRIN2A, raising the possibility that their abnormal expression contributes disproportionately to RTT. Interestingly, these genes are among the most methylated and highly affected by MeCP2 deficiency. Such “convergence” of pathways involved in different intellectual disability syndromes could have therapeutic relevance for neurodevelopmental disorders generally.

A second study published during 2021 involves SALL4 (Figure 1), a multi-zinc-finger protein that plays an important role in development and disease (e.g. SALL4 is highly expressed in many cancers with poor prognosis). We identified this protein in a screen for proteins that might interpret DNA base composition by recognising AT-rich DNA. Zinc finger cluster 4 of SALL4 specifically targets short A/T-rich motifs and recruits a partner corepressor. Inactivation of ZFC4 in embryonic stem cells leads to precocious differentiation and up-regulates AT-rich genes that are normally silenced in embryonic stem cells, thereby destabilising the pluripotent state. Our SALL4 study provides the first evidence that base composition can be read as a biological signal to regulate gene expression.

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A. A cartoon showing loss of preferential repression of AT-rich genes by SALL4 when the AT binding domain ZFC4 is mutated, leading to precocious differentiation towards a neuronal fate.

B. Microscopy of mouse embryonic stem cell nuclei showing co-localisation of wildtype SALL4 (WT) with heterochromatic foci containing AT-rich DNA (stained with DAPI). When zinc finger cluster 4 is mutated (ZFC4mut), SALL4 becomes dispersed throughout the nucleus. As a control, we show that staining with the SALL4 antibody is absent when the SALL4 gene is deleted (S4KO).