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

Abstract

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.One sentence summaryA single enzyme, TGM2, bidirectionally controls H3 monoaminylation dynamics, which, in turn, facilitate neural rhythmicity.

Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress- and antidepressant-mediated gene expression and behavior

“…An additional limitation of the current study is the possibility that our viral dominant negative approach may also impact H3Q5dop in DRN, as both marks are indeed present within this brain region (note that H3Q5his is only very weakly found within DRN (20)), although their relative stoichiometries remain unclear. Presumably, given that the proportion of serotonergic vs. dopaminergic neurons is largely skewed towards that of serotonergic cells in DRN, one might assume that the serotonylation mark would be more dominantly expressed, though this has yet to be tested empirically.…”

“…Furthermore, we hypothesize that these findings may help to explain, at least in part, the delayed efficacy of 5-HT associated ADs in both humans with MDD and preclinical rodent models. Many of our previous findings have suggested that H3 monoaminylation levels are largely dictated by intracellular donor (i.e., monoamine) concentrations (20), but once established in neuronal chromatin, it remains unclear how quickly the marks will be turned over, especially given the relatively slow kinetics of histone turnover observed in both neurons and glia (62). As such, AD treatments may function to increase 5-HT release from serotonergic neurons, thereby reducing intracellular 5-HT concentrations, eventually leading to loss, or restoration, of the mark within these cells.…”

“…In addition to its role as a neuromodulator, 5-HT was previously shown to be capable of forming covalent bonds with certain substrate proteins via transamidation by the tissue Transglutaminase 2 enzyme, a process referred to as serotonylation (17). In more recent studies, our group identified a new class of histone posttranslational modification (PTM) termed monoaminylation, whereby monoamine neurotransmitters, such as 5-HT, dopamine and histamine, can be transamidated onto histone glutamine residues (18)(19)(20)(21)(22)(23). We showed that histone H3 glutamine (Q) 5 is a primary site for these PTMs and demonstrated that H3 monoaminylation states play important roles in the regulation of neuronal transcriptional programs, both during early development/cellular differentiation and in adult brain.…”

Bioorthogonal labeling and enrichment of histone monoaminylation reveal its accumulation and regulatory function in cancer cell chromatin

“…15,17,26 The enhanced binding affinity between H3Q5ser and WDR5 can be attributed to multiple interactions, such as the cation-π stacking between R4828 of WDR5 and the indole ring of H3Q5ser. 17,27 Although this enhanced binding had no effect on the enzymatic activity of MLL1 for H3K4 methylation, the existence of H3Q5ser could stabilize H3K4me3 from dynamic turnover by profoundly inhibiting the binding and activity of H3K4me3 erasers (such as KDM5B/C and LSD1). 26 To uncover the crosstalk between H3Q5ser and H3K4me3 in colon tumor tissues, we incubated probe 1 and the extracted histone faction of colorectal cancer samples to introduce the biotin tag to serotonylated H3.…”

“…9,13,14 Recently, we elucidated the biochemical mechanism of another type of intriguing microenvironment-driven histone PTM, i.e., monoaminylation on N-terminal glutamine residue of histone H3 (H3Q5). 15,16,17 The dynamics of this modification, including its installation, removal, and replacement, are regulated by a single enzyme, transglutaminase 2 (TGM2) through a transamination reaction (Fig. 1A).…”