Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3

Chemical modifications of histones can mediate diverse DNA-templated processes including gene transcription(1–3). Here, we provide evidence for a new class of histone posttranslational modification (PTM), serotonylation of glutamine, which occurs at position 5 (Q5ser) on histone H3 in serotonin (5-hydroxytryptamine, 5-HT) producing organisms. We demonstrate that tissue Transglutaminase 2 (TGM2) can serotonylate histone H3 tri-methylated lysine 4 (H3K4me3) marked nucleosomes resulting in the presence of combinatorial H3K4me3Q5ser in vivo. H3K4me3Q5ser displays a ubiquitous pattern of tissue expression in mammals, with enrichment observed in brain and gut, two organ systems responsible for the bulk of 5-HT production. Genome-wide analyses of human serotonergic neurons, developing mouse brain and cultured serotonergic cells indicate that the mark is enriched in euchromatin, is sensitive to cellular differentiation and correlates with permissive gene expression, phenomena that are linked to the mark’s potentiation of TFIID(4–6) interactions with H3K4me3. Cells ectopically expressing an H3 mutant that cannot be serotonylated display significantly altered expression of H3K4me3Q5ser target loci leading to deficits in differentiation. Taken together, these data identify a direct role for 5-HT, independent from its contributions to neurotransmission and cellular signaling, in the mediation of permissive gene expression.