2. Academic Validation
  3. Quinone reductase 2 reads H3 serotonylation to support neuronal maturation

Quinone reductase 2 reads H3 serotonylation to support neuronal maturation

  • bioRxiv. 2026 Mar 19:2026.03.17.712426. doi: 10.64898/2026.03.17.712426.
Min Chen 1,  Celi Yang 2,  Xin Li 3 4,  Lingchun Kong 1,  Benjamin H Weekley 1,  Xiaoran Wei 1,  Jennifer C O'Chan 1,  David A Vinson 1,  Bulent Cetin 1,  Aarthi Ramakrishnan 1,  Li Shen 1,  Rongsheng Zeng 3,  Zheng Liu 4,  Juner Zhang 5,  Kaylee M Cappuccio 5,  Joshua R Sokol 5,  Erdene Baljinnyam 6,  Ruiqi Hu 1 6 7,  Kobi Rosenblum 8,  Henrik Molina 9,  Qingfei Zheng 10 11,  Yael David 12 13 14 15,  Samuele G Marro 1 6 7,  Tom W Muir 5,  Xiang David Li 4 16,  Haitao Li 2,  Ian Maze 1 17 18
Affiliations

Affiliations

  • 1 Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
  • 2 Beijing Advanced Innovation Center for Structural Biology, MOE Key Laboratory of Protein Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
  • 3 Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen 518132, China.
  • 4 Department of Chemistry, University of Hong Kong, Hong Kong SAR, China.
  • 5 Department of Chemistry, Princeton, New Jersey 08544, USA.
  • 6 Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
  • 7 Department of Stem Cell Biology and Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
  • 8 Sagol Department of Neurobiology, Natural Science Faculty, Center for Gene Manipulation in the Brain, University of Haifa, 3498838, Haifa, Israel.
  • 9 The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
  • 10 Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA.
  • 11 Institute for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA.
  • 12 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
  • 13 Tri-Institutional PhD Program in Chemical Biology, New York, New York 10065, USA.
  • 14 Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, New York 10065, USA.
  • 15 Department of Pharmacology, Weill Cornell Medicine, New York, New York 10065, USA.
  • 16 State Key Laboratory of Synthetic Chemistry, University of Hong Kong, Hong Kong SAR, China.
  • 17 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
  • 18 Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
PMID: 41890023 DOI: 10.64898/2026.03.17.712426
Abstract

Histone H3 Gln5 serotonylation (H3Q5ser) is a recently described posttranslational modification1 that plays important roles in guiding transcriptional permissiveness in brain and peripheral systems2-5. H3Q5ser has been implicated in diverse physiological and pathological processes ranging from neural differentiation1 to sensory processing6, circadian rhythmicity7, stress responsivity8, placental gene regulation9, and tumorigenesis10-19. Since H3Q5ser can occur in combination with H3 Lys4 trimethylation (H3K4me3), most mechanistic studies to date have focused on H3Q5ser's roles in modulating H3K4me3 reader interactions, where it has been shown to potentiate TAF3/TFIID binding to H3K4me31,20,21 and inhibit the recruitment of K4me3 demethylases21; however, whether H3 serotonylation functions as an autonomous chromatin signaling MARK through dedicated reader proteins has remained unknown. Here, using a combination of proteomic-, structural-, molecular-, epigenomic-, and cellular-based approaches, we demonstrate that the Quinone Reductase 2 (QR2) enzyme reads H3Q5ser independently of H3K4me3. CRISPR-Cas9-mediated disruption of H3 serotonylation or QR2's binding to the MARK in human induced pluripotent stem cell-derived neurons impairs the establishment of neuronal transcriptional programs, alters synaptic connectivity, and disrupts electrophysiological maturation. These findings thus uncover an H3 serotonylation-dependent chromatin signaling axis that is essential for human neurodevelopment.

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