Micronutrients shape FOXP2 activity: Mechanistic insights from retinoic acid, folic acid and pyrroloquinoline quinone

FOXP2 is a neurodevelopmental transcription factor that regulates genes essential for neuronal differentiation, synaptic connectivity, and speech and language. Here, we show that the small neuroactive molecules retinoic acid (RA), folic acid (FA), and pyrroloquinoline quinone (PQQ), can associate with the FOXP2 forkhead domain (FHD) and are accompanied by ligand-specific changes in protein conformation, DNA binding behaviour and transcriptional output. Through a combination of biochemical assays, fluorescence anisotropy, cellular reporter analyses, and molecular simulations, we reveal that each ligand engages FOXP2 in a structurally distinct manner that translates into specific functional outcomes. RA and FA promote a more flexible, open conformation of the DNA-bound FHD, enhancing DNA affinity and transcriptional activation, while PQQ stabilises a compact, rigid state associated with reduced transcription. These findings support the possibility that nutrient-derived ligands can fine-tune transcription factor dynamics and function through direct or context-dependent interactions, with the strongest evidence observed for RA, suggesting a mechanism by which metabolic and nutritional cues may directly influence neurodevelopmental gene regulation. This work reveals a previously unrecognised mode of transcription factor modulation by micronutrients, suggesting that dietary components may directly influence the structural and hence regulatory properties of FOXP2. This work opens new avenues for understanding nutrient-responsive transcriptional networks in the brain. • Micronutrients bind directly to the FOXP2 forkhead domain. • Micronutrients induce distinct structural shifts in FOXP2 FHD. • Retinoic acid strongly enhances FOXP2–DNA binding and activation. • Folic acid and PQQ modulate FOXP2 function in subtler, distinct ways. • DNA-bound computational modelling and dynamics reveals a shared ligand pocket near the minor groove. • Nutrient signals can tune FOXP2 dynamics and transcription suggesting that regulation is metabolically responsive.