Histone metalation: A novel layer to the epigenetic histone code

Metals exert various effects on all aspects of epigenetics. Yet, the effect metals expend on histone proteins has remained under the radar. The current review article presents histones as metal-coordinating proteins, i.e. histone metalation, with a particular focus on the redox biochemistry underlying histone metalation. Almost 60 years of research in the field compiling biochemical, structural and functional evidence is covered. We provide an overview of eighteen different metals which have been shown to be coordinated by histones: Mg, Ca, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Ru, Cd, Sn, W, Pt, Au, Hg, and Pb. Investigation on histone metalation have been hampered by the difficulty of various experimental challenges, and research has therefore mainly focused on histone peptide sequences. Nonetheless, we review evolutionary conserved metal coordination at the H2A C-tail (-S₁₂₁HH₁₂₄-) and H3-H3' (-C₁₁₀AIH₁₁₃-) dimerization interface as the two most likely coordination entities of the histone octamer. The functional implications this has on the biochemical transcription and DNA damage processes in the cell nucleus are debated. Besides, we suggest a working mechanism of histone metalation: in transcription initiation via metal accessible euchromatin sites. We discuss limitations of the current structural, biochemical and functional research which has been conducted and provide novel perspectives and opportunities. Finally, we address the remaining future challenges and open questions.