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

Lorna A. Farrelly, Robert E. Thompson, Shuai Zhao, Ashley E. Lepack, Yang Lyu, Natarajan V. Bhanu, Baichao Zhang, Yong-Hwee E. Loh, Aarthi Ramakrishnan, Krishna C. Vadodaria, Kelly J. Heard, Galina Erikson, Tomoyoshi Nakadai, Ryan M. Bastle, Bradley J. Lukasak, Henry Zebroski, Natalia Alenina, Michael Bader, Olivier Berton, Robert G. Roeder, Henrik Molina, Fred H. Gage, Li Shen, Benjamin A. Garcia, Haitao Li, Tom W. Muir and Ian Maze ()
Additional contact information
Lorna A. Farrelly: Icahn School of Medicine at Mount Sinai
Robert E. Thompson: Princeton University
Shuai Zhao: School of Medicine, Tsinghua University
Ashley E. Lepack: Icahn School of Medicine at Mount Sinai
Yang Lyu: Icahn School of Medicine at Mount Sinai
Natarajan V. Bhanu: University of Pennsylvania
Baichao Zhang: School of Medicine, Tsinghua University
Yong-Hwee E. Loh: Icahn School of Medicine at Mount Sinai
Aarthi Ramakrishnan: Icahn School of Medicine at Mount Sinai
Krishna C. Vadodaria: The Salk Institute for Biological Sciences
Kelly J. Heard: The Salk Institute for Biological Sciences
Galina Erikson: The Salk Institute for Biological Sciences
Tomoyoshi Nakadai: The Rockefeller University
Ryan M. Bastle: Icahn School of Medicine at Mount Sinai
Bradley J. Lukasak: Princeton University
Henry Zebroski: The Rockefeller University
Natalia Alenina: Max-Delbrück-Center for Molecular Medicine (MDC)
Michael Bader: Max-Delbrück-Center for Molecular Medicine (MDC)
Olivier Berton: Icahn School of Medicine at Mount Sinai
Robert G. Roeder: The Rockefeller University
Henrik Molina: The Rockefeller University
Fred H. Gage: The Salk Institute for Biological Sciences
Li Shen: Icahn School of Medicine at Mount Sinai
Benjamin A. Garcia: University of Pennsylvania
Haitao Li: School of Medicine, Tsinghua University
Tom W. Muir: Princeton University
Ian Maze: Icahn School of Medicine at Mount Sinai

Nature, 2019, vol. 567, issue 7749, 535-539

Abstract: Abstract Chemical modifications of histones can mediate diverse DNA-templated processes, including gene transcription1–3. 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 TFIID4–6 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.

Date: 2019
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DOI: 10.1038/s41586-019-1024-7

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