Phf8 histone demethylase deficiency causes cognitive impairments through the mTOR pathway

Xuemei Chen, Shuai Wang, Ying Zhou, Yanfei Han, Shengtian Li, Qing Xu, Longyong Xu, Ziqi Zhu, Youming Deng, Lu Yu, Lulu Song, Adele Pin Chen, Juan Song, Eiki Takahashi, Guang He, Lin He, Weidong Li () and Charlie Degui Chen ()
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Xuemei Chen: Shanghai Jiao Tong University
Shuai Wang: Shanghai Jiao Tong University
Ying Zhou: Shanghai Jiao Tong University
Yanfei Han: Shanghai Jiao Tong University
Shengtian Li: Shanghai Jiao Tong University
Qing Xu: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Longyong Xu: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Ziqi Zhu: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Youming Deng: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Lu Yu: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Lulu Song: Shanghai Jiao Tong University
Adele Pin Chen: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Juan Song: University of North Carolina School of Medicine
Eiki Takahashi: Research Resources Center, RIKEN Brain Science Institute
Guang He: Shanghai Jiao Tong University
Lin He: Shanghai Jiao Tong University
Weidong Li: Shanghai Jiao Tong University
Charlie Degui Chen: Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02531-y

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