Normally, CpG dinucleotides in CpG islands are not methylated and the genes are active. If CpG islands are methylated, however, they attract MeCP2 proteins, which bind additional proteins that repress gene transcription and turn the promoter off. Thus MeC2P is thought to be a key player in assembling the protein factors that silence transcription. Because MeCP2 binds to methylated CpG dinucleotides, its effects are not dependent on the primary sequence of DNA.
"One proposal for how defective or absent MeCP2 protein might cause Rett Syndrome was that, by failing to attach to methylated CpG dinucleotides, it would fail to repress inappropriate gene expression in the brain," says Kohwi-Shigematsu.
For some genes, called imprinted genes, their expression status depends on whether the gene came from the maternal or paternal allele, with the two forms often having differently methylated CpG islands at or near their promoters. A leading hypothesis of how mutated MECP2 could produce Rett Syndrome is that the mutation disrupts this imprinting mechanism.
An imprinted gene, one with a methylated promoter, is usually silent. If defective or missing MeCP2 protein were to fail to silence an imprinted allele, the expression of the gene would double. Failure to repress imprinted alleles has been implicated in several neurological disorders.
"MeCP2, the protein coded for by the MECP2 gene, is expressed in many tissues, including brains," says Kohwi-Shigematsu. "People thought it was a general repressor that regulates gene expression throughout the body. Yet the main syndrome of Rett patients pointed to neurodevelopmental problems after birth. So our first challenge was to find out which genes MeC
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Contact: Paul Preuss
paul_preuss@lbl.gov
510-486-6249
DOE/Lawrence Berkeley National Laboratory
19-Dec-2004