Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
Nat Commun. 2017 May 9;8:15142. doi: 10.1038/ncomms15142.
PHF8 is a histone demethylase with specificity for repressive modifications. While mutations of PHF8 have been associated with cognitive defects and cleft lip/palate, its role in mammalian development and physiology remains unexplored. Here, we have generated a Phf8 knockout allele in mice to examine the consequences of Phf8 loss for development and behaviour. Phf8 deficient mice neither display obvious developmental defects nor signs of cognitive impairment. However, we report a striking resiliency to stress-induced anxiety- and depression-like behaviour on loss of Phf8. We further observe misregulation of serotonin signalling within the prefrontal cortex of Phf8 deficient mice and identify the serotonin receptors Htr1a and Htr2a as direct targets of PHF8. Our results clarify the functional role of Phf8 in mammalian development and behaviour and establish a direct link between Phf8 expression and serotonin signalling, identifying this histone demethylase as a potential target for the treatment of anxiety and depression.
PHF8 是一种具有特异性的组蛋白去甲基化酶，针对抑制性修饰。虽然 PHF8 的突变与认知缺陷和唇裂/腭裂有关，但它在哺乳动物发育和生理学中的作用仍未被探索。在这里，我们在小鼠中生成了一个 Phf8 敲除等位基因，以研究 Phf8 缺失对发育和行为的影响。Phf8 缺陷型小鼠既没有明显的发育缺陷，也没有认知障碍的迹象。然而，我们报告说，Phf8 缺失的小鼠在应激诱导的焦虑和抑郁样行为方面表现出惊人的弹性。我们进一步观察到 Phf8 缺陷型小鼠前额叶皮质中 5-羟色胺信号的失调，并确定 5-羟色胺受体 Htr1a 和 Htr2a 是 PHF8 的直接靶标。我们的研究结果阐明了 Phf8 在哺乳动物发育和行为中的功能作用，并在 Phf8 表达和 5-羟色胺信号之间建立了直接联系，将这种组蛋白去甲基化酶确定为治疗焦虑和抑郁的潜在靶点。
