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Adrian Bird

Co-workers:

Co-workers: Beatrice Alexander-Howden, Kyla Brown, Justyna Cholewa-Waclaw, John Connelly, Dina De Sousa, Jacky Guy, Martha Koerner, Sabine Lagger, Matthew Lyst, Cara Merusi, Timo Quante, Gabriele Schweikert, Jim Selfridge, Ruth Shah, Christine Struthers, Rebekah Tillotson, Elisabeth Wachter
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DNA methylation and CpG islands

Adrian gives a brief overview of his research.

We study the biological significance of the dinucleotide DNA sequence CpG, which exists in chemically distinct forms due to marking by DNA methylation. CpG frequency is highly variable in the genome, being widely under-represented except in “CpG islands”, which mark the regulatory regions of most human genes. Our recent research established that CpG islands are landing pads for proteins that recognise CpG in an unmethylated state and predispose chromatin structure towards an “active” state. Recent work has developed this theme by asking what features shared by all CpG islands are required to insure that chromatin adopts this structure. We find that in addition to CpG frequency itself, DNA base composition plays an important role in CpG island function.

MeCP2 is a protein that recognises methylated CpG sites in the genome. Mutations in the MECP2 gene, many of which change only one amino acid, cause the autism spectrum disorder Rett syndrome. Mapping of these miss-sense mutations shows that most are clustered within either the DNA binding domain (MBD) or the NCoR interaction domain (NID; Figure 1A). Modelling of a NID mutation (R306C) in mice abolished the MeCP2-NCoR interaction (Figure 1B) and led to a Rett-like phenotype. NID mutations also prevent MeCP2 from taking TBL1 from the cell cytoplasm to methylated sites in the nucleus (Figure 1C), but they do not affect the ability of MeCP2 itself to bind to methylated DNA. On the other hand, the T158M miss-sense mutation, which is in the MBD, abolished the binding of MeCP2 to foci of DNA methylation. It seems that proper functioning of the MeCP2 protein depends upon its dual ability to bind methylated DNA and NCoR. Loss of the interaction with either of these binding partners leads to Rett syndrome.

We earlier showed that restoration of MeCP2 protein to mice that had developed in its absence led to reversal of many symptoms of Rett syndrome. This suggested that Rett syndrome in humans might be a curable disorder. To pursue this possibility, we collaborated with Dr Gail Mandel and colleagues of Oregon University to test whether gene therapy using adeno-associated viruses might be able to deliver the missing gene. Administration of virus indeed led to a significant improvement in Rett-like symptoms. Much remains to be done before this type of therapy could be attempted in humans, but the results sustain the idea that there may one day be a meaningful treatment for Rett syndrome.

Selected publications:

Selected Publications: McLeod, F., Ganley, R., Williams, L., Selfridge, J., Bird, A., and Cobb, S.R. (2013). Reduced seizure threshold and altered network oscillatory properties in a mouse model of Rett syndrome. Neuroscience 231, 195-205.

Lyst, M.J., Ekiert, R., Ebert, D.H., Merusi, C., Nowak, J., Selfridge, J., Guy, J., Kastan, N.R., Robinson, N.D., de Lima Alves, F., Rappsilber, J., Greenberg, M.E. and Bird, A. (2013). Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat Neurosci 16, 898-902.

Bird, A. (2013). Genome biology: not drowning but waving. Cell 154, 951-952.


A                                                                                                    B

   

C                                                              D

Figure 1. A. Miss-sense mutations in the methyl-CpG binding protein MeCP2 that cause Rett syndrome are predominantly in two clusters: the methyl-CpG binding domain (MBD) and the NCoR interaction domain (NID). B. A common Rett mutation in the NID (R306C) prevents the interaction between MeCP2 and protein components of the NCoR transcriptional silencing complex. C. The NCoR component TBL1 normally localises to the cytoplasm when over-expressed, but it is taken to DAPI bright spots by co-expressed WT MeCP2. MeCP2[R306C], however, has lost the ability to localise TBL1. D. Like normal MeCP2 (WT), R306C mutant MeCP2 localises to sites of densely methylated DNA (DAPI-stained bright spots) in mouse NeuN-positive neurons. MeCP2[T158M] cannot bind to methylated DNA in vitro or efficiently localise to DAPI bright spots in living cells.