Methylation of mammalian DNA can lead to repression of transcription and alteration of chromatin structure. Recent evidence suggests that both effects are the result of an Interaction between the methylated sites and methylCpG-binding proteins (MeCPs). MeCPl has previously been detected in crude nuclear extracts. Here we report the identification, purification, and cDNA cloning of a novel YeCP called MeCP2. Unlike MeCPl, the new protein is able to bind to DNA that contains a single methyl-CpG pair. By staining with an antibody, we show that the distribution of MeCP2 along the chromosomes parallels that of methyl-CpG. In mouse, for example, MeCP2 is concentrated in pericentromeric heterochromatin, which contains a large fraction (about 40%) of all genomlc Smethylcytosine.