Chromatin-Binding Protein PHF6 Regulates Activity-Dependent Transcriptional Networks to Promote Hunger Response
Chromatin-Binding Protein PHF6 Regulates Activity-Dependent Transcriptional Networks to Promote Hunger Response
复制标题
染色质结合蛋白 PHF6 调节活性依赖性转录网络以促进饥饿反应
DOI：
10.1016/j.celrep.2020.02.085
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发表时间：
2020-03-17
期刊：
影响因子：
8.8
通讯作者：
Huang, Ju
中科院分区：
文献类型：
--
作者：
Gan, Linhua;Sun, Jingjing;Huang, Ju
了解适应性行为背后的活性依赖性基因转录机制是神经元亚型解析的挑战。利用Agouti-related peptide（AgRP）神经元中的细胞类型特异性分子分析，我们揭示了深刻的饥饿诱导的转录变化在很大程度上依赖于植物同源结构域指蛋白6（PHF 6），一种在AgRP神经元中富集的转录抑制因子。在饱食小鼠中PHF 6的丢失导致饥饿状态转移的转录谱，而饥饿未能进一步诱导PHF 6缺陷的AgRP神经元中快速和稳健的活性依赖性基因转录。我们发现，PHF 6结合到一个子集的立即早期基因（IEG）的启动子，这种染色质结合是动态调节的饥饿状态。PHF 6的消耗降低了饥饿驱动的进食动机，并使小鼠在重复禁食-再喂食条件下抵抗体重增加。我们的工作确定了一个神经元亚型特异性转录抑制因子，它在不同的营养状态下调节转录谱，并使适应性饮食行为成为可能。
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.