Function Of BFL Syndrome Protein PHF6 In Feeding Behavior And Metabolic Homeostasis

B?rjeson-Forssman-Lehmann(BFL)syndrome protein plant homeodomain finger protein 6(PHF6)is intellectual disability related protein.In this study,we find that PHF6 is enriched in hypothalamic agouti-related peptide(Ag RP)neurons.Loss of PHF6 in Ag RP neurons in satiated mice results in a hunger-state-shifting transcriptional profile.Hunger fails to further induce a rapid and robust activity-dependent gene transcription,especially the immediate early genes(IEGs),in PHF6-deficient Ag RP neurons.We also reveal that PHF6 binds to the promoters of a subset of immediate-early genes and that this chromatin binding is dynamically regulated by hunger state.Hunger triggered the decrease in PHF6 occupancy on the promoters of the IEGs and allowed for IEG rapid induction.Despite the unchanged body weight and homeostatic eating under normal ad libitum feeding conditions,Phf6^{c KO} mice displayed a significant reduction in hunger-driven motivational eating.Depletion of PHF6 in Ag RP neurons decreases hunger-driven feeding motivation and makes the mice resistant to body weight gain under repetitive fasting-refeeding conditions.Thus,Phf6^{c KO} mice were resistant to body weight gain while on the yo-yo diet.This work identifies a neuronal subtype-specific transcriptional repressor that modulates transcriptional profiles in different nutritional states and enables adaptive eating behavior,and explores its role in metabolic regulation.This work provides a new perspective for people to understand the way of chromatin-binding proteins in animal instinctive behavior regulation.