Chemical modifications of histones can mediate diverse DNA-templated processes, including gene transcription1,2,3. Here we provide evidence for a class of histone post-translational modification, serotonylation of glutamine, which occurs at position 5 (Q5ser) on histone H3 in organisms that produce serotonin (also known as 5-hydroxytryptamine (5-HT)). We demonstrate that tissue transglutaminase 2 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 H3K4me3Q5ser nucleosomes are enriched in euchromatin, are sensitive to cellular differentiation and correlate with permissive gene expression, phenomena that are linked to the potentiation of TFIID4,5,6 interactions with H3K4me3. Cells that ectopically express a H3 mutant that cannot be serotonylated display significantly altered expression of H3K4me3Q5ser-target loci, which leads to deficits in differentiation. Taken together, these data identify a direct role for 5-HT, independent from its contributions to neurotransmission and cellular signalling, in the mediation of permissive gene expression.
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Data from ChIP-seq and RNA-seq experiments have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database under accession numbers GSE106495 and GSE117910. The mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium via the PRIDE48,49 partner repository with the dataset identifier PXD008106. Additional raw data files are available at https://chorusproject.org under project no. 1513. We declare that the data supporting findings for this study are available within the article and Supplementary Information (Supplementary Fig. 1). Related data are available from the corresponding author upon reasonable request. No restrictions on data availability apply.
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We thank R. Cagan (ISMMS), J. Coplan (SUNY Downstate) and C. Tamminga (UTSW) for providing Drosophila, macaque and human samples, respectively, for analysis of H3K4me3Q5ser (Fig. 1e), and G. Johnson (University of Rochester Medical Center) for wild-type and catalytically dead TGM2 constructs. This work was supported by grants from the National Institutes of Health: DP1 DA042078 (I.M.), R01 MH116900 (I.M.), R21 DA044767 (I.M.), P50 MH096890 (I.M.), R37 GM086868 (T.W.M.), P01 CA196539 (T.W.M. and B.A.G.), R01 GM110174 (B.A.G.), R21 DA040837 (B.A.G.), R01 CA129325 (R.G.R.), R01 CA204639 (R.G.R.), T32 DA007135 (R.M.B.), as well as awards from: MQ Mental Health Research Charity, MQ15FIP100011 (I.M.), Alfred P. Sloan Foundation, Fellowship in Neuroscience (I.M.), the JPB Foundation (F.H.G.), the Bob and Mary Jane Engman Foundation (F.H.G.), the Volkswagen Foundation (N.A.) and the National Natural Science Foundation of China (31430020 and 31621092, H.L.).
Nature thanks Tatiana Kutateladze and the other anonymous reviewer(s) for their contribution to the peer review of this work.