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

Cell Rep. 2020 Mar 17;30(11):3717-3728.e6. 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.

Keywords: AgRP neuron; BFLS; Börjeson-Forssman-Lehmann syndrome; IEGs; PHF6; activity-dependent gene transcription; hunger-driven feeding behavior; immediate-early genes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agouti-Related Protein / metabolism
  • Animals
  • Chromatin / metabolism*
  • Diet
  • Down-Regulation / genetics
  • Feeding Behavior
  • Gene Ontology
  • Gene Regulatory Networks / genetics*
  • Genes, Immediate-Early
  • Hunger / physiology*
  • Hypothalamus / metabolism
  • Mice, Inbred C57BL
  • Motivation
  • Neurons / metabolism*
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Satiety Response
  • Weight Gain


  • Agouti-Related Protein
  • Chromatin
  • Phf6 protein, mouse
  • Repressor Proteins