Wednesday, July 2, 2025 7/2/2025

Development of a Chemical Biology Toolbox to Investigate Histone Monoaminylation

Award Number: R35GM150676
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Development of a Chemical Biology Toolbox to Investigate Histone Monoaminylation - The dynamics of covalent post-translational modifications (PTMs) on histones are a key mechanism in epigenetic regulation. Histone PTMs (also known as the “histone code”) are dynamically introduced and removed by “writer” and “eraser” enzymes, while the recognition of these PTM makers by “reader” proteins controls the activation and suppression of specific genes, motivating downstream epigenetic effects. Histone monoaminylation (i.e., H3 serotonylation and dopaminylation) is a newly identified epigenetic marker that plays an important role in regulating neuronal transcription, both during development and in the adult brain. Transglutaminase 2 (TGM2) has been proved to serve as the writer enzyme for this emerging histone PTM, which installs serotonin or dopamine onto the N-terminal glutamine residue of H3 (i.e., H3Q5) through transamidation. However, the eraser and reader for H3Q5 monoaminylation still remain elusive. In our recent study, we applied chemical biology approaches to understand the dynamic control of histone monoaminylation and unexpectedly discovered that the installation, removal, and replacement of this modification are all mediated by a single enzyme, TGM2. The biochemical mechanism of this novel regulation is attributed to the formation of a reactive thioester complex between TGM2 and H3 that can be attacked by nucleophiles (such as diverse monoamine metabolites). Based on this unique enzymology, we identified an unreported histone monoaminylation, H3Q5 histaminylation, and found that this new epigenetic marker promotes neural rhythmicity through epigenetic regulations. In this research program, we will develop a series of chemical probes that can orthogonally label and enrich different histone monoaminylations. Utilizing these probes, we will identify new types of monoaminylations (especially the ones caused by gut microbiome-derived monoamines) both in vitro and in vivo. Thereafter, we will demonstrate the pathophysiological roles of these epigenetic makers. We will also design and synthesize photocrosslinker- containing monoaminylated peptides as chemical baits to covalently capture possible readers that recognize and bind the target monoaminylations. The epigenetic functions of these identified readers will be further validated both in vitro and in vivo. Finally, we will employ the chemical probes developed in this study to characterize the non-histone targets (such as transcription factors) of monoaminylations and elucidate their potential roles in epigenetics and chromatin biology. Together, these findings will expand the categories of histone code and open a new door towards understanding the interplay between monoamine metabolism (from either host cells or gut microbiome) and cell fate regulation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $400,941 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Biomedical Research and Research Training	002	4	5/26/2025	NON-COMPETING CONTINUATION	$392,500
2025	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	003	2	6/5/2025	NON-COMPETING CONTINUATION	-$1
2025	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Biomedical Research and Research Training	004	3	6/5/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1
2025	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Biomedical Research and Research Training	001	3	4/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$358,087
2025	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	2	4/24/2025	NON-COMPETING CONTINUATION	-$349,646
														Subtotal = $400,941

Issue Date FY: 2024 ( Subtotal = $384,084 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	2	5/2/2024	NON-COMPETING CONTINUATION	$384,084
														Subtotal = $384,084

Issue Date FY: 2023 ( Subtotal = $384,365 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	1	7/18/2023	NEW	$384,365
														Subtotal = $384,365

Grand Total All Awards = $1,169,390

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Development of a Chemical Biology Toolbox to Investigate Histone Monoaminylation

Award Number: R35GM150676

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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