H2A.Z's ‘social’ network: functional partners of an enigmatic histone variant

The histone variant H2A.Z has been extensively studied to understand its manifold DNA-based functions. In the past years, researchers identified its specific binding partners, the 'H2A.Z interactome', that convey H2A.Z-dependent chromatin changes. Here, we summarize the latest findings regarding vertebrate H2A.Z-associated factors and focus on their roles in gene activation and repression, cell cycle regulation, (neuro)development, and tumorigenesis. Additionally, we demonstrate how protein-protein interactions and post-translational histone modifications can fine-tune the complex interplay of H2A.Z-regulated gene expression. Last, we review the most recent results on interactors of the two isoforms H2A.Z.1 and H2A.Z.2.1, which differ in only three amino acids, and focus on cancer-associated mutations of H2A and H2A.Z, which reveal fascinating insights into the functional importance of such minuscule changes.