Decision letter: KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands

Abstract

Gene expression in eukaryotic cells can be controlled in a number of different ways, including various epigenetic mechanisms that do not involve making changes to DNA sequences that define the genes themselves. A well-known epigenetic mechanism for silencing genes in vertebrates is DNA methylation—the addition of a methyl group (CH3) to cytosine, which is one of the four bases found in the DNA. Methylation is thought to silence genes by preventing transcription factors from binding to the DNA, and also by recruiting proteins that inhibit the transcription of DNA. DNA methylation occurs naturally throughout the genome, mostly at positions where cytosine is bonded to guanine to form a CpG dinucleotide. While the cytosine bases in most CpG dinucleotides are methylated, there are short stretches of DNA known as CpG islands that contain a high proportion of unmethylated CpG dinucleotides. These islands contain a large number of cytosine and guanine bases, and they are often found at or near transcription start sites. The lack of methylation at CpG islands has long been assumed to have a passive role in gene expression, leaving the DNA easily accessible and available for transcription factors to bind and initiate transcription. However, recent work suggests that CpG islands may have a more active role. In particular, it has been shown that specific proteins bind to CpG islands to create chromatin environments that are more favourable for the initiation of gene expression. Moreover, a subset of CpG islands can also bind polycomb-group proteins, including the polycomb repressive complex 1 (PRC1) that silence gene expression. These complexes have an important role in the regulation of genes during early development in animals, but the mechanism by which PRC1 recognizes CpG islands in mammals has remained enigmatic. Farcas et al. now reveal that a protein, KDM2B (FBXL10), can recognize CpG islands and recruit PRC1 to them. To achieve this, KDM2B encodes a DNA binding domain that specifically recognizes non-methylated CpG dinucleotides. By interacting biochemically with a variant PRC1 complex, KDM2B then nucleates PRC1 at CpG islands, and PRC1 activity silences certain polycomb target genes in embryonic stem cells. Surprisingly, Farcas et al. also find low but appreciable levels of PRC1 at most CpG islands genome-wide, in addition to the high levels of PRC1 at selected islands: this suggests that KDM2B may sample the whole genome to find CpG islands where PRC1 can establish silencing. An improved understanding of the polycomb repressive system, and the role of CpG islands within it, could lead to new insights into the role of epigenetic mechanisms in mammalian development.