Quinone reductase 2 <i>reads</i> H3 serotonylation to support neuronal maturation

Histone H3 Gln5 serotonylation (H3Q5ser) is a recently described posttranslational modification ¹ that plays important roles in guiding transcriptional permissiveness in brain and peripheral systems ^2-5 . H3Q5ser has been implicated in diverse physiological and pathological processes ranging from neural differentiation ¹ to sensory processing ⁶ , circadian rhythmicity ⁷ , stress responsivity ⁸ , placental gene regulation ⁹ , and tumorigenesis ^10-19 . 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 <i>reader</i> interactions, where it has been shown to potentiate TAF3/TFIID binding to H3K4me3 ^1,20,21 and inhibit the recruitment of K4me3 demethylases ²¹ ; however, whether H3 serotonylation functions as an autonomous chromatin signaling mark through dedicated <i>reader</i> 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 <i>reads</i> 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.