Chromatin-Binding Protein PHF6 Regulates Activity-Dependent Transcriptional Networks to Promote Hunger Response

• Published in: Cell reports (Cambridge) 2020-03, Vol.30 (11), p.3717-3728.e6
• Main Authors: Gan, Linhua, Sun, Jingjing, Yang, Shuo, Zhang, Xiaocui, Chen, Wu, Sun, Yiyu, Wu, Xiaohua, Cheng, Cheng, Yuan, Jing, Li, Anan, Corbett, Mark A., Dixon, Mathew P., Thomas, Tim, Voss, Anne K., Gécz, Jozef, Wang, Guang-Zhong, Bonni, Azad, Li, Qian, Huang, Ju
• Format: Article
• Language: English
• Subjects: activity-dependent gene transcription; Agouti-Related Protein - metabolism; AgRP neuron; Animals; BFLS; Börjeson-Forssman-Lehmann syndrome; Chromatin - metabolism; Diet; Down-Regulation - genetics; Feeding Behavior; Gene Ontology; Gene Regulatory Networks - genetics; Genes, Immediate-Early; Hunger - physiology; hunger-driven feeding behavior; Hypothalamus - metabolism; IEGs; immediate-early genes; Mice, Inbred C57BL; Motivation; Neurons - metabolism; PHF6; Promoter Regions, Genetic - genetics; Protein Binding; Repressor Proteins - genetics; Repressor Proteins - metabolism; Satiety Response; Weight Gain
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.02.085

Understanding the mechanisms of activity-dependent gene transcription underlying adaptive behaviors is challenging at neuronal-subtype resolution. Using cell-type specific molecular analysis in agouti-related peptide (AgRP) neurons, we reveal that the profound hunger-induced transcriptional changes greatly depend on plant homeodomain finger protein 6 (PHF6), a transcriptional repressor enriched in AgRP neurons. Loss of PHF6 in the satiated mice results in a hunger-state-shifting transcriptional profile, while hunger fails to further induce a rapid and robust activity-dependent gene transcription in PHF6-deficient AgRP neurons. We reveal that PHF6 binds to the promoters of a subset of immediate-early genes (IEGs) and that this chromatin binding is dynamically regulated by hunger state. Depletion of PHF6 decreases hunger-driven feeding motivation and makes the mice resistant to body weight gain under repetitive fasting-refeeding conditions. Our work identifies a neuronal subtype-specific transcriptional repressor that modulates transcriptional profiles in different nutritional states and enables adaptive eating behavior. [Display omitted] •PHF6 is a transcriptional repressor regulating IEG expression in AgRP neurons•PHF6-chromatin binding is dynamically regulated by different nutritional states•Loss of PHF6 in AgRP neurons impairs hunger-induced gene transcription•Loss of PHF6 in AgRP neurons decreases hunger-driven feeding motivation Gan et al. show that PHF6 is a transcriptional repressor enriched in AgRP neurons and regulates immediate-early gene (IEG) expression. Depletion of PHF6 in AgRP neurons decreases hunger-driven feeding motivation and makes the mice resistant to body weight gain under repetitive fasting/refeeding conditions.