Hyperconserved CpG domains underlie Polycomb-binding sites.
Comparative genomics of CpG dinucleotides, which are targets of DNA methyltransferases in vertebrate genomes, has been constrained by their evolutionary instability and by the effect of methylation on their mutation rates. We compared the human and chimpanzee genomes to identify DNA sequence signatures correlated with rates of mutation at CpG dinucleotides. The new signatures were used to develop robust comparative genomics of CpG dinucleotides in heterogeneous regions and to identify genomic domains that have anomalous CpG divergence rates. The data showed that there are approximately 200 genomic regions where CpG distributions are far more conserved than predicted. These hyperconserved CpG domains largely coincide with domains bound by Polycomb repressive complex 2 in undifferentiated human embryonic stem cells and are almost exclusively present near genes whose products are involved in the regulation of embryonic development. Several domains were experimentally shown to be unmethylated at different developmental stages. These data indicate that particular evolutionary patterns and distinct sequence properties on scales much larger than standard transcription factor-binding sites may play an important role in Polycomb recruitment and transcriptional regulation of key developmental genes.
Tanay
Amos
A
Center for Studies in Physics and Biology, The Rockefeller University, New York, NY 10021, USA. atanay@mail.rockefeller.edu
O'Donnell
Anne H
AH
Damelin
Marc
M
Bestor
Timothy H
TH
D000818:Animals; D001665:Binding Sites; D017124:Conserved Sequence; D018899:CpG Islands; D053595:Embryonic Stem Cells / Q000378:metabolism; D044127:Epigenesis, Genetic; D019143:Evolution, Molecular; D016678:Genome; D015894:Genome, Human; D006801:Humans; D002679:Pan troglodytes; D063146:Polycomb-Group Proteins; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics*; D013045:Species Specificity; D014157:Transcription Factors / Q000378:metabolism
D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D014157:Transcription Factors