The “Ins and Outs and What-Abouts” of H2A.Z: A Tribute to C. David Allis

In 2023, the brilliant chromatin biologist C. David Allis passed away leaving a large void in the scientific community and broken hearts in his family and friends. With this review, we want to tribute Dave’s enduring inspiration by focusing on the histone variant H2A.Z, a nucleosome component he was the first to discover as hv1 in Tetrahymena. We summarize the latest findings from the past five years regarding the mammalian H2A.Z histone, focusing on its deposition and eviction mechanisms, its roles in transcriptional regulation, DNA damage repair, chromatin structure organization and embryonic development as well as how its deregulation or mutation(s) of its histone chaperones contribute to disease development. As Dave liked to say ‘Every amino acid matters’; the discovery and characterization of functionally different H2A.Z’s isoforms, which vary only in three amino acids, prove him – once again – right.