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 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 () and Ian Maze ()
Additional contact information
Qingfei Zheng: The Ohio State University
Benjamin H. Weekley: Icahn School of Medicine at Mount Sinai
David A. Vinson: Icahn School of Medicine at Mount Sinai
Shuai Zhao: Tsinghua University
Ryan M. Bastle: Icahn School of Medicine at Mount Sinai
Robert E. Thompson: Princeton University
Stephanie Stransky: Albert Einstein College of Medicine
Aarthi Ramakrishnan: Icahn School of Medicine at Mount Sinai
Ashley M. Cunningham: Icahn School of Medicine at Mount Sinai
Sohini Dutta: Icahn School of Medicine at Mount Sinai
Jennifer C. Chan: Icahn School of Medicine at Mount Sinai
Giuseppina Salvo: Icahn School of Medicine at Mount Sinai
Min Chen: Icahn School of Medicine at Mount Sinai
Nan Zhang: The Ohio State University
Jinghua Wu: The Ohio State University
Sasha L. Fulton: Icahn School of Medicine at Mount Sinai
Lingchun Kong: Icahn School of Medicine at Mount Sinai
Haifeng Wang: Tsinghua University
Baichao Zhang: Tsinghua University
Lauren Vostal: Memorial Sloan Kettering Cancer Center
Akhil Upad: Memorial Sloan Kettering Cancer Center
Lauren Dierdorff: Icahn School of Medicine at Mount Sinai
Li Shen: Icahn School of Medicine at Mount Sinai
Henrik Molina: The Rockefeller University
Simone Sidoli: Albert Einstein College of Medicine
Tom W. Muir: Princeton University
Haitao Li: Tsinghua University
Yael David: Memorial Sloan Kettering Cancer Center
Ian Maze: Icahn School of Medicine at Mount Sinai

Nature, 2025, vol. 637, issue 8047, 974-982

Abstract: Abstract Histone H3 monoaminylations at Gln5 represent an important family of epigenetic marks in brain that have critical roles in permissive gene expression1–3. We previously demonstrated that serotonylation4–10 and dopaminylation9,11–13 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.

Date: 2025
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DOI: 10.1038/s41586-024-08371-3

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