The Nucleus: Express Yourself

Methylation of cytosine in CpG sequences is an epigenetic modification of DNA that is associated with a repressive chromatin state. Large clusters of CpG sequences known as CpG islands (CGIs) tend to be unmethylated and are found near active transcription start sites. However, a subset of CGIs corresponds to binding regions for the repressive polycomb complex in mammals. In the past couple of years, it has become clear that certain chromatin-modifying activities are directed to nonmethylated CGIs. So far, each of these activities has been associated with active transcription. The Set1 histone H3 lysine 4 methyltransferase complex subunit CFP1 and KDM2A, a histone H3 lysine 36 demethylase, both contain a zinc finger CxxC DNA-binding domain (ZF-CxxC) that preferentially binds unmethylated CGIs. In two separate studies, Robert Klose and Kristian Helin and their colleagues looked at the binding and function of KDM2B (a paralog of KDM2A also known as FBXL10) to see whether it binds CGIs like KDM2A. The ChIP-seq results from both groups show that, like KDM2A, KDM2B binds to CGIs across the genome, and Klose and colleagues see that KDM2B is more robustly represented at CGIs that are bound by the polycombrepressive complex, PRC1, which ubiquitinates histone H2A at lysine 119. It was previously shown that KDM2B can be part of an alternative PRC1 complex, and both groups find that KDM2B binds a specific variant of PRC1 via a subunit called NSPc1 (or PCGF1) and that the ZF-CxxCmotif of KDM2B is responsible for targeting these complexes to unmethylated CGIs. The ZF-CxxC motif of KDM2B is important for histone H2A ubiquitination, and loss of KDM2B reactivates a subset of polycomb targets. Helin and colleagues go on to show that KDM2B, like other PRC1 components, is important for proper differentiation of mouse embryonic stem cells. These findings add to the complexity of polycomb targeting in mammals, which lack a defined polycomb response element, and support an emerging concept that PRC1 targeting is not always dependent on the histone H3 lysine 27 trimethylation activity of PRC2. Farcas, A.M., et al. (2012). eLIFE. Published online December 18, 2012. http://dx.doi.org/10.7554/eLife.00205. Wu, X., et al. (2013). Mol. Cell. Published online February 7, 2013. http://dx.doi.org/10.1016/j.molcel.2013.01.016.