Bidirectional histone monoaminylation dynamics regulate neural rhythmicity

Qingfei Zheng; Benjamin H Weekley; David A Vinson; Shuai Zhao; Ryan M Bastle; Robert E Thompson; Stephanie Stransky; Aarthi Ramakrishnan; Ashley M Cunningham; Sohini Dutta; Jennifer C Chan; Giuseppina Di Salvo; Min Chen; Nan Zhang; Jinghua Wu; Sasha L Fulton; Lingchun Kong; Haifeng Wang; Baichao Zhang; Lauren Vostal; Akhil Upad; Lauren Dierdorff; Li Shen; Henrik Molina; Simone Sidoli; Tom W Muir; Haitao Li; Yael David; Ian Maze

doi:10.1038/s41586-024-08371-3

Bidirectional histone monoaminylation dynamics regulate neural rhythmicity

Nature. 2025 Jan 8. doi: 10.1038/s41586-024-08371-3. Online ahead of print.

Authors

Qingfei Zheng^#^{1

2}, Benjamin H Weekley^#³, David A Vinson^#³, Shuai Zhao^#⁴, Ryan M Bastle^#³, Robert E Thompson⁵, Stephanie Stransky⁶, Aarthi Ramakrishnan³, Ashley M Cunningham³, Sohini Dutta³, Jennifer C Chan³, Giuseppina Di Salvo^{3

7}, Min Chen³, Nan Zhang¹, Jinghua Wu^{1

2}, Sasha L Fulton³, Lingchun Kong³, Haifeng Wang⁴, Baichao Zhang⁴, Lauren Vostal^{8

9}, Akhil Upad^{8

9}, Lauren Dierdorff³, Li Shen³, Henrik Molina¹⁰, Simone Sidoli⁶, Tom W Muir⁵, Haitao Li^{11

12

13}, Yael David^{14

15

16

17}, Ian Maze^{18

19

20}

Affiliations

¹ Department of Radiation Oncology, College of Medicine and Center for Cancer Metabolism, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
² Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN, USA.
³ Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, School of Basic Medical Sciences, Tsinghua University, Beijing, China.
⁵ Department of Chemistry, Princeton University, Princeton, NJ, USA.
⁶ Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA.
⁷ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands.
⁸ Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁹ Tri-Institutional PhD Program in Chemical Biology, New York, NY, USA.
¹⁰ The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY, USA.
¹¹ State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, School of Basic Medical Sciences, Tsinghua University, Beijing, China. [email protected].
¹² SXMU-TM Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, China. [email protected].
¹³ Tsinghua-Peking Center for Life Sciences, Beijing, China. [email protected].
¹⁴ Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
¹⁵ Tri-Institutional PhD Program in Chemical Biology, New York, NY, USA. [email protected].
¹⁶ Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY, USA. [email protected].
¹⁷ Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. [email protected].
¹⁸ Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
¹⁹ Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
²⁰ Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].

^# Contributed equally.

PMID: 39779849
DOI: 10.1038/s41586-024-08371-3

Abstract

Histone H3 monoaminylations at Gln5 represent an important family of epigenetic marks in brain that have critical roles in permissive gene expression^1-3. We previously demonstrated that serotonylation^4-10 and dopaminylation^9,11-13 of Gln5 of histone H3 (H3Q5ser and H3Q5dop, respectively) are catalysed by transglutaminase 2 (TG2), and alter both local and global chromatin states. Here we found that TG2 additionally functions as an eraser and exchanger of H3 monoaminylations, including H3Q5 histaminylation (H3Q5his), which displays diurnally rhythmic expression in brain and contributes to circadian gene expression and behaviour. We found that H3Q5his, in contrast to H3Q5ser, inhibits the binding of WDR5, a core member of histone H3 Lys4 (H3K4) methyltransferase complexes, thereby antagonizing methyltransferase activities on H3K4. Taken together, these data elucidate a mechanism through which a single chromatin regulatory enzyme has the ability to sense chemical microenvironments to affect the epigenetic states of cells, the dynamics of which have critical roles in the regulation of neural rhythmicity.