Abstract
H2A.Z is a H2A‐type histone variant essential for many aspects of cell biology, ranging from gene expression to genome stability. From deuterostomes, H2A.Z evolved into two paralogues, H2A.Z.1 and H2A.Z.2, that differ by only three amino acids and are encoded by different genes (H2AFZ and H2AFV, respectively). Despite the importance of this histone variant in development and cellular homeostasis, very little is known about the individual functions of each paralogue in mammals. Here, we have investigated the distinct roles of the two paralogues in cell cycle regulation and unveiled non‐redundant functions for H2A.Z.1 and H2A.Z.2 in cell division. Our findings show that H2A.Z.1 regulates the expression of cell cycle genes such as Myc and Ki‐67 and its depletion leads to a G1 arrest and cellular senescence. On the contrary, H2A.Z.2, in a transcription‐independent manner, is essential for centromere integrity and sister chromatid cohesion regulation, thus playing a key role in chromosome segregation.
Highlights
Nucleosomes form the basic unit of eukaryotic chromatin and consist of 146 DNA base pairs wrapped around an octamer of histone proteins
The data show that: (i) the siRNAs are specific for each paralogue; (ii) in HeLa cells, as in many other systems, H2A.Z.1 is expressed at a much higher level than H2A.Z.2; (iii) the removal of one form does not interfere with the expression level of the other (Fig EV1A and C, and D) or histone H2A (Fig EV1B)
Despite the established importance of the histone variant H2A.Z in many aspects of cell biology and growing evidence suggesting differential roles for the H2A.Z.1 and H2A.Z.2 paralogues in chromatin organisation and function, the majority of the studies far have focussed on H2A.Z as a single variant and very little is known about their individual roles during cell cycle in mammals
Summary
Nucleosomes form the basic unit of eukaryotic chromatin and consist of 146 DNA base pairs wrapped around an octamer of histone proteins. Canonical histones are incorporated into nucleosomes during DNA replication but histone variants, encoded by separate genes, are typically incorporated throughout the cell cycle (Filipescu et al, 2013; Skene & Henikoff, 2013; Turinetto & Giachino, 2015). H2A.Z is present as a single variant until early deuterostomes when two H2A.Z paralogues appear: H2A.Z.1 and H2A.Z.2; they differ by only three amino acids and are encoded by the H2AFZ and H2AFV genes, respectively (Coon et al, 2005). H2A.Z.2 has two splice variants: H2A.Z.2.1 and H2A.Z.2.2, where H2A.Z.2.2 has a shorter docking domain and forms highly unstable nucleosomes (Bonisch et al, 2012)
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