Random deposition of histone variants: A cellular mistake or a novel regulatory mechanism?

Despite the fact that it has been intensively studied during the last decade, the function of the histone variant H2A.Z remains enigmatic. In the last few years, we and others have determined the localization of H2A.Z in various organisms. These studies have revealed that H2A.Z occupies different well defined regions in the genome. Interestingly, H2A.Z occupies the promoters and regulatory regions of active genes, as well as constitutive and facultative heterochromatin. The localization of H2A.Z on genomic regions with so diverse functions suggests that the roles of H2A.Z are multiple, only increasing the mystery around this molecule. The way H2A.Z finds its way into these regions is not fully understood but mechanisms that direct the specific incorporation of H2A.Z in promoters and enhancers have been well described. In this "point of view," we will review our recent work suggesting that non-targeted incorporation, coupled to targeted depletion of H2A.Z, is a novel mechanism for localizing H2A.Z to some regions. We propose that the various functions of H2A.Z may be a consequence of the mechanism used for its incorporation, as well as its interactions with other histone variants.