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

Linhua Gan, Jingjing Sun, Shuo Yang, Xiaocui Zhang, Wu Chen, Yiyu Sun, Xiaohua Wu, Cheng Cheng, Jing Yuan, Anan Li, Mark A. Corbett, Mathew P. Dixon, Tim Thomas, Anne K. Voss, Jozef Gecz, Guang Zhong Wang, Azad Bonni, Qian Li, Ju Huang

Research output: Contribution to journalArticle

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.

LanguageEnglish
Pages3717-3728.e6
JournalCell Reports
Volume30
Issue number11
DOIs
Publication statusPublished - 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)

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