Repression of genes by DNA methylation depends on CpG density and promoter strength: evidence for involvement of a methyl-CpG binding protein.
Repression of transcription from densely methylated genes can be mediated by the methyl-CpG binding protein MeCP-1 (Boyes and Bird, 1991). Here we have investigated the effect of methylation on genes with a low density of methyl-CpG. We found that sparse methylation could repress transfected genes completely, but the inhibition was fully overcome by the presence in cis of an SV40 enhancer. Densely methylated genes, however, could not be reactivated by the enhancer. In vitro studies showed that the sparsely methylated genes bound weakly to MeCP-1 and that binding interfered with transcription. In the absence of available MeCP-1, methylation had minimal effects on transcription. From these and other results we propose that sparsely methylated genes form an unstable complex with MeCP-1 which prevents transcription when the promoter is weak. This complex can be disrupted by a strong promoter, thereby allowing the methylated gene to be transcribed.
Boyes
J
J
Research Institute for Molecular Pathology, Vienna, Austria.
Bird
A
A
D000818:Animals; D001665:Binding Sites; D015254:DNA Modification Methylases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015257:DNA-Cytosine Methylases / Q000378:metabolism; D005786:Gene Expression Regulation; D005914:Globins / Q000235:genetics; D008745:Methylation; D051379:Mice; D008957:Models, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013539:Simian virus 40 / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection
D004268:DNA-Binding Proteins; D005914:Globins; D015254:DNA Modification Methylases; D015257:DNA-Cytosine Methylases