Deciphering the Enigma of the Histone H2A.Z-1/H2A.Z-2 Isoforms: Novel Insights and Remaining Questions

Abstract

The replication independent (RI) histone H2A.Z is one of the more extensively studied variant members of the core histone H2A family, which consists of many replication dependent (RD) members. The protein has been shown to be indispensable for survival, and involved in multiple roles from DNA damage to chromosome segregation, replication, and transcription. However, its functional involvement in gene expression is controversial. Moreover, the variant in several groups of metazoan organisms consists of two main isoforms (H2A.Z-1 and H2A.Z-2) that differ in a few (3–6) amino acids. They comprise the main topic of this review, starting from the events that led to their identification, what is currently known about them, followed by further experimental, structural, and functional insight into their roles. Despite their structural differences, a direct correlation to their functional variability remains enigmatic. As all of this is being elucidated, it appears that a strong functional involvement of isoform variability may be connected to development.

Histone variants at a glance

“…Chordates encode two H2A.Z proteins ( Eirín-López et al, 2009 ), H2A.Z.1 and H2A.Z.2, which differ by three conserved amino acids (reviewed in Cheema et al, 2020 ). H2A.Z.1-knockout animals die during early development ( Faast et al, 2001 ) and H2A.Z.2 is required for melanocyte development in zebrafish ( Raja et al, 2020 ).…”

Epigenetic Modulation via the C-Terminal Tail of H2A.Z

“…H2A.Z (1) is an all-important histone variant involved in the regulation of diverse and basic cell functions, involving activating as well as repressive effects that have proved difficult to reconcile in a unified model. These include: transcription (2-6), DNA replication (7), heterochromatin organization (3,6,8,9), DNA repair (10,11), cell differentiation and cell cycle (12,13), epithelial mesenchymal transition in embryonic development and cancer (14). H2A.Z is upregulated in melanoma, breast, prostate, colorectal, liver, bladder and lung cancer (3,15), it is an important player in intestinal epithelial cell homeostasis (13), Wnt, Notch, Nanog, Gli1 signaling (13,16-18), in central nervous system development and functioning (19-22).…”

“…H2A.Z is upregulated in melanoma, breast, prostate, colorectal, liver, bladder and lung cancer (3,15), it is an important player in intestinal epithelial cell homeostasis (13), Wnt, Notch, Nanog, Gli1 signaling (13,16-18), in central nervous system development and functioning (19-22). H2A.Z has about 60% identity to canonical H2A and comprises approximately 5% of the total H2A histones in vertebrates (1,6,23).…”

“…Two isoforms of H2A.Z are known to exist, encoded by separate genes, which differ by only 3 amino acids: H2A.Z1 and H2A.Z2 (43,44). The two isotypes have indispensable and selective functions during development (45,46) and appear to have distinct roles in different forms of cancer (6,47). Crystallographic analysis (48) revealed structural differences within the histone fold domain that are without any apparent influence on the stability of the core particles harboring the different isoforms, even though they exhibit differential in vivo mobility features, as pointed out in (6).…”

“…The two isotypes have indispensable and selective functions during development (45,46) and appear to have distinct roles in different forms of cancer (6,47). Crystallographic analysis (48) revealed structural differences within the histone fold domain that are without any apparent influence on the stability of the core particles harboring the different isoforms, even though they exhibit differential in vivo mobility features, as pointed out in (6). On the other hand, alternative splicing gives rise to the hypervariant H2A.Z2.2 which is shorter than H2A.Z1 or Z2 by 14 amino acids and markedly destabilizes the nucleosomes relative to H2A.Z1 or H2A (49).…”