Abstract
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.
Original language | English |
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Pages (from-to) | 3717-3728.e6 |
Journal | Cell Reports |
Volume | 30 |
Issue number | 11 |
DOIs | |
Publication status | Published - 17 Mar 2020 |
Keywords
- AgRP neuron
- BFLS
- Börjeson-Forssman-Lehmann syndrome
- IEGs
- PHF6
- activity-dependent gene transcription
- hunger-driven feeding behavior
- immediate-early genes
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)