# Serotonylation of the Histone H3 tail: Uncovering the function of a novel epigenetic mark

> **NIH NIH F32** · PRINCETON UNIVERSITY · 2020 · $20,871

## Abstract

PROJECT SUMMARY
Histone PTMs are implicated in a variety of nuclear processes including gene regulation, DNA repair and
chromatin structure. Misregulation of these chemical decorations have immense consequences for human
biology and have the potential to drive disease states. Recently, we have uncovered a new histone PTM that
involves the covalent addition of the neurotransmitter, serotonin, on to the N-terminal tail of histone H3.
Interestingly, in compelling preliminary data, we have shown that the installation of serotonin onto glutamine 5
is catalyzed by the enzyme tissue transglutaminase 2 (TGM2). Importantly, the misregulation of TGM2 has been
implicated in cancer and neurodegenerative disease highlighting its importance. Our preliminary data also
highlights the use of a newly developed, highly specific validated antibody for H3Q5ser, to show that
serotonylation is highly enriched in serotonin-producing organisms and that the modification is increased in
post-differentiated raphe-medulloblastoma cells (RN46A-B14). While the mechanism by which serotonin is
added has been uncovered, its role while present on H3 is unknown. The major goal of this proposal is to shed
light on the function of H3Q5ser and also interrogate if it is a dynamic PTM.
To do this, I plan to employ semisynthetic techniques that have been developed and optimized within the Muir
lab to chemically construct serotonylated mononucleosomes containing a photo crosslinker. Once in hand, I will
utilize them to capture the proteins that closely interact with the H3Q5ser mark, termed `readers'. This
experiment will serve as a major benchmark to begin to understand how H3Q5ser contributes to regulate the
functional output of chromatin. The second major goal of this research program is to determine if H3Q5ser can
be removed, and if so, how? Interestingly, TGM2, the same enzyme responsible for serotonin deposition, is
known to possess deaminase activity. If H3Q5ser is removed by TGM2 then a point mutation (Gln to Glu) would
be left in its place. This possibility is particularly interesting giving the propensity of histone tail mutations in
cancer.
Together, these experiments aim to elucidate the role of H3Q5ser as a new histone H3 PTM. The data generated
by the proposed research will be of immense interest to the chromatin and chemical biology community in
illuminating the function of a novel histone PTM.

## Key facts

- **NIH application ID:** 10004138
- **Project number:** 5F32GM129935-03
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Kelly Chuh
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $20,871
- **Award type:** 5
- **Project period:** 2018-09-01 → 2020-12-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004138

## Citation

> US National Institutes of Health, RePORTER application 10004138, Serotonylation of the Histone H3 tail: Uncovering the function of a novel epigenetic mark (5F32GM129935-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10004138. Licensed CC0.

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