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
Affiliations
Linhua Gan
Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Jingjing Sun
Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Shuo Yang
Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Xiaocui Zhang
Core Facility of Basic Medical Sciences, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Wu Chen
Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
Yiyu Sun
Department of Neurosurgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China
Xiaohua Wu
Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Cheng Cheng
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA
Jing Yuan
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
Anan Li
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
Mark A. Corbett
Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Mathew P. Dixon
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
Tim Thomas
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, The University of Melbourne, VIC, Australia
Anne K. Voss
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, The University of Melbourne, VIC, Australia
Jozef Gécz
Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
Guang-Zhong Wang
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
Azad Bonni
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA
Qian Li
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; Corresponding author
Ju Huang
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; Corresponding author
Summary: 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. : 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. Keywords: PHF6, hunger-driven feeding behavior, AgRP neuron, activity-dependent gene transcription, immediate-early genes, IEGs, Börjeson-Forssman-Lehmann syndrome, BFLS
