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 Gécz; Guang-Zhong Wang; Azad Bonni; Qian Li; Ju Huang

doi:10.1016/j.celrep.2020.02.085

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.

Authors

Linhua Gan¹, Jingjing Sun¹, Shuo Yang¹, Xiaocui Zhang², Wu Chen³, Yiyu Sun⁴, Xiaohua Wu¹, Cheng Cheng⁵, Jing Yuan⁶, Anan Li⁶, Mark A Corbett⁷, Mathew P Dixon⁸, Tim Thomas⁹, Anne K Voss⁹, Jozef Gécz⁷, Guang-Zhong Wang¹⁰, Azad Bonni⁵, Qian Li¹¹, Ju Huang¹²

Affiliations

¹ Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Core Facility of Basic Medical Sciences, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
³ Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
⁴ Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China.
⁵ Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁶ Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China; HUST-Suzhou Institute for Brainmatics, Suzhou 215125, China.
⁷ Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
⁸ The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
⁹ The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, The University of Melbourne, VIC, Australia.
¹⁰ CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.
¹¹ Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai 201210, China. Electronic address: liqian@shsmu.edu.cn.
¹² Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai 201210, China. Electronic address: juhuang@shsmu.edu.cn.

PMID: 32187544
DOI: 10.1016/j.celrep.2020.02.085

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.

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

Substances

Agouti-Related Protein
Chromatin
Phf6 protein, mouse
Repressor Proteins