H2A.Z.2.2 is an alternatively spliced histone H2A.Z variant that causes severe nucleosome destabilization

Authors:
  • KSKatrin Schneider
    Katrin Schneider
  • SPSebastian Pünzeler
    Sebastian Pünzeler
  • SWSonja M. Wiedemann
    Sonja M. Wiedemann
  • CBChristina Bielmeier
    Christina Bielmeier
  • MBMarco Bocola
    Marco Bocola
  • WKWolfgang Kuegel
    Wolfgang Kuegel
  • JNJürgen Neumann
    Jürgen Neumann
  • EKElisabeth Kremmer
    Elisabeth Kremmer
  • HLHeinrich Leonhardt
    Heinrich Leonhardt
  • MMMatthias Mann
    Matthias Mann
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Abstract
The histone variant H2A.Z has been implicated in many biological processes, such as gene regulation and genome stability. Here, we present the identification of H2A.Z.2.2 (Z.2.2), a novel alternatively spliced variant of histone H2A.Z and provide a comprehensive characterization of its expression and chromatin incorporation properties. Z.2.2 mRNA is found in all human cell lines and tissues with highest levels in brain. We show the proper splicing and in vivo existence of this variant protein in humans. Furthermore, we demonstrate the binding of Z.2.2 to H2A.Z-specific TIP60 and SRCAP chaperone complexes and its active replication-independent deposition into chromatin. Strikingly, various independent in vivo and in vitro analyses, such as biochemical fractionation, comparative FRAP studies of GFP-tagged H2A variants, size exclusion chromatography and single molecule FRET, in combination with in silico molecular dynamics simulations, consistently demonstrate that Z.2.2 causes major structural changes and significantly destabilizes nucleosomes. Analyses of deletion mutants and chimeric proteins pinpoint this property to its unique C-terminus. Our findings enrich the list of known human variants by an unusual protein belonging to the H2A.Z family that leads to the least stable nucleosome known to date.

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