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Adrian Bird

Co-workers:

Kyla Brown, Helene Cheval, 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, 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 two base-pair DNA sequence CG. Despite being extremely short, this dinucleotide has several characteristics of a genomic signalling module. Firstly, it occurs in several chemically modified forms due to the presence or absence of methylation (or its oxidised derivative hydroymethylcytosine) on the cytosine residue. Secondly, it varies greatly in frequency in the genome, ranging from one per 10 base pairs on average in so-called CpG island promoters to one per 100 base pairs in bulk genomic DNA. Thirdly, we know of proteins that specifically interact with either the methylated or non-methylated forms of MeCP2 leading to altered chromatin structure.

Cfp1, for example, is a protein that binds to non-methylated CG and is part of the multi-protein SET1 complex, which methylates lysine 4 of histone H3 (H3K4me3). Previously we showed that introduction of an artificial CG cluster into the genome caused Cfp1 to be recruited resulting in a novel domain of H3K4me3. This suggests a potential function for CpG islands – namely to facilitate gene expression by facilitating a chromatin structure that favours transcription. More recently we studied embryonic stem cells lacking Cfp1 and found that many CpG islands lose their characteristic H3K4me3, but also ectopic peaks of this histone modification appear at transcriptional enhancers.

We also work on the protein MeCP2, which binds to the methylated form of CG. Mutations in this protein cause the autism spectrum disorder Rett syndrome. To understand the molecular basis of this neurological condition, we use genetic and biochemical approaches to study MeCP2. Previously, we found that MeCP2 binds to methylated DNA in living cells and loss of this interaction is a specific cause of Rett Syndrome. Recent work has identified a second functionally significant MeCP2 binding partner: the transcriptional co-repressor complex NCoR1. Mutations that prevent the interaction with NCoR cause Rett syndrome, suggesting that MeCP2 acts as an essential bridge between methylated DNA and this complex (Fig. 1). The idea that inhibition of transcription is a key function of MeCP2 is supported by the results of a collaboration with the laboratory of Prof Michael Greenberg (Harvard Medical School). This work showed that binding to NCoR is regulated by phosphorylation of MeCP2 that is dependent upon neuronal activity. As a consequence of this, induction of specific genes is reduced. Our current research is targeted at finding out more about the kinds of transcription regulated by MeCP2.

Selected publications:

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.

Ebert, D.H., Gabel, H.W., Robinson, N.D., Kastan, N.R., Hu, L.S., Cohen, S., Navarro, A.J., Lyst, M.J., Ekiert, R., Bird, A.P. and Greenberg, M.E. (2013). Activity-dependent phosphorylation of MECP2 threonine 308 regulates interaction with NcoR. Nature.

Clouaire, T., Webb, S., Skene, P., Illingworth, R., Kerr, A., Andrews, R., Lee, J.H., Skalnik, D. and Bird, A. (2012). Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells. Genes Dev 26, 1714-1728.