Bird, Adrian P

Skene, Peter J.

2011-02-01T10:16:06Z

2011-02-01T10:16:06Z

2010

MeCP2 was initially identified as an abundant protein in the brain, with an affinity for methylated DNA in vitro. Interestingly, both deficiency and excess of the protein leads to severe neurological problems, such as Rett syndrome, which is the result of mutations in the MECP2 gene. Subsequent transfection experiments showed that MeCP2 can recruit corepressor complexes and inhibit gene expression in vivo. MeCP2 was therefore thought to repress specific gene targets and the aetiology of Rett syndrome was proposed to result from aberrant gene expression in the MeCP2-deficient brain. Although gene expression is perturbed in the Mecp2-null mouse brain, few specific targets have been verified and alternative hypotheses for MeCP2 function have been put forward. Previous binding studies have also failed to clearly identify MeCP2 targets. To shed light on these matters, a novel technique was generated to isolate neuronal and glial nuclei and established that the amount of MeCP2 is unexpectedly high in neurons, with an abundance approaching that of the histone octamer. Chromatin immunoprecipitation experiments on mature mouse brain showed widespread binding of MeCP2, consistent with its high abundance, tracking the methyl-CpG density of the genome. MeCP2 deficiency results in global changes in neuronal chromatin structure, including elevated histone acetylation and a doubling of histone H1. The mutant brain also shows elevated transcription of repetitive elements, which are distributed throughout the mouse genome. Based on this data, we propose that MeCP2 binds genome wide and suppresses spurious transcription through binding in a DNA methylation dependent manner.

http://hdl.handle.net/1842/4737

en

The University of Edinburgh

Schmiedeberg, L., Skene, P., Deaton, A., and Bird, A. (2009). A temporal threshold for formaldehyde crosslinking and fixation. PLoS One 4, e4636.

Thomson, J.P., Skene, P.J., Selfridge, J., Clouaire, T., Guy, J., Webb, S., Kerr, A.R.W., Deaton, A., Andrews, R., James, K.D., et al. (2010). CpG islands influence chromatin structure via the CpGbinding protein Cfp1. Nature 464, 1082-1086.

MeCP2

Rett syndrome

glial nuclei

binding

Global analysis of the methyl-CpG binding protein MeCP2

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy