When nonspecialized cells move on to more differentiated fates, members of the Polycomb protein family detach from DNA for differentiation, allowing the genes to be expressed. Also important to differentiation is the way that DNA is packaged around structures called histones, or cellular structures that spool DNA and help control which stretches can be translated into proteins. Now, Laurie Boyer and colleagues at the Massachusetts Institute of Technology in Cambridge report that histone variant H2AZ, which is essential for embryonic development, regulates a set of genes similar to those controlled by Polycomb protein Suz12. This suggests that H2AZ and the Polycomb proteins are cooperating so that, when the time is right, cells can quickly activate the genes that control early differentiation1.

Working in mouse embryonic stem (ES) cells, the researchers found that, unlike other histones, H2AZ occupied the promoter regions of over 1,600 genes active in ES cells. These genes belonged to categories that would be expected to promote differentiation. The researchers compared these patterns to other DNA-binding proteins and found a striking similarity to Suz12. Not only did H2AZ and Suz12 control similar genes, but also they both occupied the genes in analogous regions, such as the promoter region into the coding region, or, in the case of the HOX genes, across several contiguous gene clusters.

Further tests showed that if H2AZ was depleted, Suz12 was also less likely to bind to those genes, and the affected genes were expressed at higher rates. H2AZ was not necessary for pluripotency or self-renewal, but it was required for differentiation.

Though H2AZ is redistributed within the genome as cells differentiate, how H2AZ is recruited to regions within ES cells and how H2AZ and Polycomb proteins cooperate is also unclear. However, together they seem to be able to form a sensitive switch to cause cells to commit to more differentiated fates.