Transglutaminase 3 is a Histone Monoaminylation Writer

Histone monoaminylation, including serotonylation, dopaminylation, and histaminylation, is an emerging class of epigenetic modifications that regulates gene transcription in diverse physiological and disease contexts. Histone H3 glutamine 5 (H3Q5) was the first identified and remains a major site of monoaminylation on core histones. Mechanistically, monoaminylation involves the formation of an isopeptide bond between a substrate glutamine and a monoamine metabolite through a reversible transamidation reaction catalyzed by transglutaminases (TGs). Among the nine members of the human TG family, TG2 has been established as the major writer of H3Q5 monoaminylation. Here, we identify TG3 as an additional histone monoaminylation writer capable of catalyzing H3Q5 histaminylation (H3Q5his).