Quinone reductase 2 reads H3 serotonylation to support human cortical neuron development

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Abstract
Histone H3 Gln5 serotonylation (H3Q5ser) is a posttranslational modification that guides transcriptional permissiveness in the brain and periphery. Because it can co-occur with H3K4me3, prior studies focused on its modulation of H3K4me3 readers , leaving open whether H3Q5ser acts as an autonomous chromatin mark. Using proteomic, structural, molecular, epigenomic, and cellular approaches, we show that Quinone reductase 2 (QR2), previously known only as a cytosolic enzyme, reads H3Q5ser independently of H3K4me3. QR2 recognizes the serotonyl group through its FAD-dependent quinone-binding pocket, discriminating against unmodified H3, H3K4me3, and other monoaminyl marks. In human iPSC-derived neurons, CRISPR-Cas9 disruption of H3 serotonylation or QR2 binding impairs transcriptional programs, synaptic connectivity, and electrophysiological maturation. In cortical organoids, these disruptions cause progenitor over-proliferation at the expense of excitatory neurons and uncouple POU2F1-linked regulatory elements from the excitatory neuron maturation program. Together, these findings reveal an H3 serotonylation-QR2 signaling axis essential for human neurodevelopment.

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