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. H2A.Z is involved in gene activation and repression, partly through interaction with post-translational modification (PTM) writer and eraser complexes (directly or through mediators). Focusing on PTMs with regard to the histone code hypothesis and the H2A.Z interactome will shed light on H2A.Z's multitude of functions. More studies display distinct functions for H2A.Z.1 and H2A.Z.2.1 partly through specific interactors, even though they only differ in three amino acids. Focusing on how their binding specificity is achieved will highlight the importance of every amino acid. H2A.Z and its interactors [e.g., PWWP Domain Containing 2A (PWWP2A) and ZNF512B] are emerging as novel regulators in early development and neurodevelopment, associate with diseases as well as cancer development, and offer new therapeutic potential. [ABSTRACT FROM AUTHOR]