Journal Article

Phf8 histone demethylase deficiency causes cognitive impairments through the mTOR pathway

Song, Lulu, Chen, Xuemei, Zhu, Ziqi, Wang, Shuai, Li, Shengtian, Zhou, Ying, Chen, Charlie Degui, Deng, Youming, Chen, Adele Pin, He, Lin, Li, Weidong, Xu, Longyong, Takahashi, Eiki, He, Guang, Song, Juan, Xu, Qing, Yu, Lu, Han, Yanfei

2018

Overview

Epigenomic abnormalities caused by genetic mutation in epigenetic regulators can result in neurodevelopmental disorders, deficiency in neural plasticity and mental retardation. As a histone demethylase, plant homeodomain finger protein 8 ( Phf8 ) is a candidate gene for syndromal and non-specific forms of X-chromosome-linked intellectual disability (XLID). Here we report that Phf8 knockout mice displayed impaired learning and memory, and impaired hippocampal long-term potentiation (LTP) without gross morphological defects. We also show that mTOR signaling pathway is hyperactive in hippocampus in Phf8 knockout mouse. Mechanistically, we show that demethylation of H4K20me1 by Phf8 results in transcriptional suppression of RSK1 and homeostasis of mTOR signaling. Pharmacological suppression of mTOR signaling with rapamycin in Phf8 knockout mice recovers the weakened LTP and cognitive deficits. Together, our results indicate that loss of Phf8 in animals causes deficient learning and memory by epigenetic disruption of mTOR signaling, and provides a potential therapeutic drug target to treat XLID. Mutations in PHF8 gene are genetically associated with X-linked mental retardation. Here, Chen et al. show that Phf8 KO mouse have cognitive and synaptic plasticity impairment, and pharmacological inhibition of mTOR signaling can partially alleviate such defects.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/19 / 38/61 / 38/77 / 631/208/176 / 64/60 / 692/617/375 / Abnormalities / Animals / Cognitive ability / Cognitive Dysfunction - genetics / Cognitive Dysfunction - metabolism / Cognitive Dysfunction - physiopathology / Demethylation / Epigenetics / Female / Gene Expression Profiling / Hippocampus / Hippocampus - metabolism / Hippocampus - physiopathology / Histone Demethylases - deficiency / Histone Demethylases - genetics / Homeobox / Homeostasis / Humanities and Social Sciences / Learning / Long-term potentiation / Long-Term Potentiation - genetics / Maze Learning - physiology / Memory / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / Motor Activity - genetics / Motor Activity - physiology / multidisciplinary / Neurodevelopmental disorders / Neuroplasticity / Pharmacology / Rapamycin / Regulators / Ribosomal protein S6 kinase / Rodents / Science / Science (multidisciplinary) / Signal Transduction / Signaling / TOR protein / TOR Serine-Threonine Kinases - genetics / TOR Serine-Threonine Kinases - metabolism / Transcription / Transcription Factors - deficiency / Transcription Factors - genetics