Histone monoaminylation dynamics are regulated by a single enzyme and promote neural rhythmicity

Histone H3 monoaminylations at glutamine(Q) 5 represent an important family of epigenetic markers in neurons that play critical roles in the mediation of permissive gene expression. We previously demonstrated that H3Q5 serotonylation(ser) and dopaminylation(dop) are catalyzed by the Transglutaminase 2 (TGM2) enzyme. Here, we found that TGM2 additionally functions as an eraser and re-writer of H3 monoaminylations, and identified a new class of this modification, H3Q5 histaminylation(his), which displayed dynamic diurnal expression in brain and contributed to neural rhythmicity. We found that H3Q5his, versus H3Q5ser, inhibited binding of the MLL1 complex to the H3 N-terminus and attenuated its methyltransferase activity on H3 lysine(K) 4. We determined that H3Q5 monoaminylation dynamics are dictated by local monoamine concentrations, which are sensed by TGM2. This noncanonical mechanism indicated that histone monoaminylations can be established and removed by a single enzyme based upon its sensing of cellular microenvironments. ### Competing Interest Statement The authors have declared no competing interest.