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  3. The histone core domain evolves at single-residue resolution to directly orchestrate transcription

The histone core domain evolves at single-residue resolution to directly orchestrate transcription

  • Cell Rep. 2025 Aug 26;44(8):116079. doi: 10.1016/j.celrep.2025.116079.
Zachary H Harvey 1,  Kathryn M Stevens 2,  Jian Yi Kok 3,  Akihisa Osakabe 4,  Jiaying Liu 5,  Tobias Warnecke 6,  Frédéric Berger 7
Affiliations

Affiliations

  • 1 Gregor Mendel Institute, Austrian Academy of Sciences, Vienna, Austria. Electronic address: zachary.harvey@gmi.oeaw.ac.at.
  • 2 MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK.
  • 3 Gregor Mendel Institute, Austrian Academy of Sciences, Vienna, Austria; Vienna BioCenter PhD Program, a Doctoral School of the University of Vienna and the Medical University of Vienna, 1030 Vienna, Austria.
  • 4 Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
  • 5 Gregor Mendel Institute, Austrian Academy of Sciences, Vienna, Austria.
  • 6 MRC Laboratory of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK; Trinity College, Oxford, UK; Department of Biochemistry, University of Oxford, Oxford, UK. Electronic address: tobias.warnecke@bioch.ox.ac.uk.
  • 7 Gregor Mendel Institute, Austrian Academy of Sciences, Vienna, Austria. Electronic address: frederic.berger@gmi.oeaw.ac.at.
PMID: 40737126 DOI: 10.1016/j.celrep.2025.116079
Abstract

Nucleosomes are thought to be structural barriers to transcription, establishing a restrictive ground state that must be destabilized for gene expression. However, structural insights have revealed that transcription can proceed in the presence of nucleosomes, suggesting that this model is incomplete. Here, we reconstituted H2A.Z sequences resulting from more than a billion years of eukaryotic evolution in a single synthetic host system, interrogating their impact on transcription. We identified single-residue substitutions within the ultra-conserved core domain loop 2 (L2) of H2A.Z as sufficient to confer emergent properties and drive neofunctionalization. Such L2 neomorphs acquired a direct interaction with transcription elongation factor Spt6, rewiring gene expression by tuning polymerase processivity. We conclude that even minimal changes in histone sequences can transform their function, underscoring the evolutionary potential of the histone core domain to drive regulatory innovation and highlighting a previously unappreciated role of the histone core domain in transcriptional regulation.

Keywords

CP: Molecular biology; H2A.Z; L2; Spt6; chromatin; evolution; transcription.

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