近期论文

Phf8 histone demethylase deficiency causes cognitive impairments through the mTOR pathway.(IF=12.353)

 2018 Jan 9;9(1):114. doi: 10.1038/s41467-017-02531-y.

Chen X1,2,3Wang S1Zhou Y1Han Y1,4Li S1Xu Q2Xu L2Zhu Z2Deng Y2Yu L2Song L1Chen AP2Song J5Takahashi E6He G1He L1Li W7Chen CD8.

Author information

1.Bio-X Institutes, Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
2.State Key Laboratory of Molecular Biology, Shanghai Key laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
3.Department of Anesthesiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
4.Discipline of Neuroscience and Department of Anatomy and Physiology, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
5.Department of Pharmacology and Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC, 27514, USA.
6.Research Resources Center, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
7.Bio-X Institutes, Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China. liwd@sjtu.edu.cn.
8.State Key Laboratory of Molecular Biology, Shanghai Key laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China. cdchen@sibcb.ac.cn.
 

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.

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