Adrian Bird

Lab members

Beatrice Alexander-Howden, Christian Belton, Kashyap Chhatbar, Justyna Cholewa-Waclaw, John Connelly, Dina De Sousa, Laura FitzPatrick, Jacky Guy, Matthew Lyst, Raphael Pantier, Katie Paton, Jim Selfridge, Konstantina Skourti-Stathaki, Christine Struthers

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MeCP2 and Rett syndrome

In 2017 we significantly advanced our understanding of the function of the chromosomal protein MeCP2. This protein, which we discovered in 1992, has been the subject of intense study since the finding that mutations within it cause the profound neurological disorder Rett syndrome. Despite these efforts, its precise role has remained uncertain, with several independent hypotheses in circulation. We originally proposed that a primary role is to target sites of DNA methylation and the evidence in favour of this from several research groups has strengthened significantly during the year. A prominent cluster of Rett-causing missense mutations co-localises with the methyl-CpG binding domain and causes its inactivation. We showed that in addition to the canonical binding site mCG, MeCP2 also targets the trinucleotide mCAC, which is abundant in neurons. In addition to methylated DNA, MeCP2 has been linked with numerous protein partners. Of particular interest, a discrete region that binds to the TBL1/R1 subunits of the NCoR and SMRT co- repressor complexes coincides with a cluster of Rett syndrome mutations. Using X-ray crystallography in a collaboration with Atlanta Cook, we found that the four amino acids mutated in Rett syndrome make intimate contact with the TBL1/R1 surface. This finding makes it highly likely that loss of this specific interaction is a root cause of the disorder.

These results add to the weight of evidence supporting the “bridge hypothesis”, whereby MeCP2 recruits the corepressor complexes based on the density of methylated sites in the genome. Re-analysis of chromatin immunoprecipitation data confirms the predictions of this model and, further, provides evidence that transcriptional inhibition at gene loci is proportional to the density of methylated binding sites. Since the great majority of Rett syndrome mutations inactivate either the DNA binding domain or the corepressor interaction domain, we speculated that these domains alone, which amount to only 32% of the full-length protein, would be sufficient to fulfil key functions of MeCP2. The results strongly support this hypothesis, as the Mecp2 “minigene” prevents Rett-like phenotypes in mice. Interestingly, injection of the minigene in an adeno-associated virus vector rescued mice that lacked endogenous MeCP2. This raises the possibility that the truncated MeCP2 might be used therapeutically for gene therapy. With our collaborator Stuart Cobb, also at Edinburgh University, we are exploring this possibility further.

Selected publications:

Tillotson, R., Selfridge, J., Koerner, M.V., Gadalla, K.K.E., Guy, J., De Sousa, D., Hector, R.D., Cobb, S.R., and Bird, A. (2017) Radically truncated MeCP2 rescues Rett syndrome-like neurological defects. Nature. 550(7676):398-401.

Lagger, S., Connelly, J.C., Schweikert, G., Webb, S., Selfridge, J., Ramsahoye, B.H., Yu, M., He, C., Sanguinetti, G., Sowers, L.C., Walkinshaw, M.D., and Bird, A. (2017) MeCP2 recognizes cytosine methylated tri- nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain. PLoS Genet. 13(5):e1006793.

Kruusvee, V., Lyst, M.J., Taylor, C., Tarnauskaite, Z., Bird, A.P., and Cook A.G. (2017) Structure of the MeCP2-TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders. Proc Natl Acad Sci U S A. 114(16):E3243-E50.