Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Core Facility of Basic Medical Sciences, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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.
理解适应性行为背后的活动依赖性基因转录机制在神经元亚型分辨率上具有挑战性。通过在 Agouti 相关肽 (AgRP) 神经元中进行细胞类型特异性分子分析，我们揭示了强烈的饥饿诱导的转录变化在很大程度上依赖于富含 AgRP 神经元的植物同源结构域手指蛋白 6 (PHF6)，作为转录抑制剂。在饱腹的小鼠中敲除 PHF6 会导致饥饿状态的转录谱发生转变，而饥饿状态无法进一步诱导 PHF6 缺陷型 AgRP 神经元中快速而强烈的活性依赖性基因转录。我们揭示 PHF6 结合到一组即时早期基因 (IEGs) 的启动子上，并且这种染色质结合受饥饿状态的动态调控。PHF6 的耗竭会降低饥饿驱动的摄食动机，并使小鼠在反复禁食-再喂食条件下不易增重。我们的工作确定了一种神经元亚型特异性转录抑制剂，它可以调节不同营养状态下的转录谱，并使动物能够适应进食行为。
