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Epigenetics

Can one enzyme put histamine on histones and take it off?

Zheng Q, Weekley BH, Vinson DA, et al. · Nature · 2025

Open access · cc by · source: Europe PMC

Transglutaminase 2 not only installs serotonin/dopamine on histone H3Q5 but also erases and swaps those marks; histaminylation (H3Q5his) rises and falls over the day, blocks WDR5, and helps set neural circadian gene expression and behavior.

Study at a glance

Design
Animal / in-vitro — Biochemical, genomic, and mouse work showing TG2 writes/erases H3Q5 monoaminylations, including rhythmic H3Q5his in TMN
N
N=25 · Multiple assays; example in vivo n = 12 zolpidem vs 13 vehicle mice plus TMN-focused molecular time courses
Population
Biochemical systems, mouse brain (especially histaminergic TMN), and circadian/behavioral assays
Outcome
H3Q5ser/dop/his dynamics, WDR5/H3K4 methylation antagonism, circadian gene expression and locomotor rhythmicity

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Key findings

TG2 acts as eraser/exchanger as well as writer. H3Q5his is diurnally rhythmic in brain (enriched in histaminergic TMN, the only HDC+ region) and, unlike H3Q5ser, inhibits WDR5 binding and thereby H3K4 methyltransferase activity, linking monoamine microenvironments to neural rhythmicity.

Methodology

Combined enzymology, chromatin binding, TMN-focused genomics, and mouse behavior to test whether TG2 erases/exchanges H3Q5 monoaminylations and whether H3Q5his is rhythmic and functionally distinct from H3Q5ser.

Limitations

Mouse and in vitro chromatin biochemistry cannot yet show that targeting H3Q5his would treat human circadian or psychiatric disorders.

How this study connects

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