Phf8 histone demethylase deficiency causes cognitive impairments through the mTOR pathway

被引：167

作者：

Chen, Xuemei ^{[1
,2
,3
,4
]}

Wang, Shuai ^{[1
,2
]}

Zhou, Ying ^{[1
,2
]}

Han, Yanfei ^{[1
,2
,5
,6
]}

Li, Shengtian ^{[1
,2
]}

Xu, Qing ^{[3
]}

Xu, Longyong ^{[3
]}

Zhu, Ziqi ^{[3
]}

Deng, Youming ^{[3
]}

Yu, Lu ^{[3
]}

Song, Lulu ^{[1
,2
]}

Chen, Adele Pin ^{[3
]}

Song, Juan ^{[7
,8
]}

Takahashi, Eiki ^{[9
]}

He, Guang ^{[1
,2
]}

He, Lin ^{[1
,2
]}

Li, Weidong ^{[1
,2
]}

Chen, Charlie Degui ^{[3
]}

机构：

[1] Shanghai Jiao Tong Univ, Minist Educ, BioX Inst, Key Lab Genet Dev & Neuropsychiatr Disorders, 800 Dongchuan Rd, Shanghai 200240, Peoples R China

[2] Shanghai Jiao Tong Univ, Brain Sci & Technol Res Ctr, 800 Dongchuan Rd, Shanghai 200240, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Key Lab Mol Androl, State Key Lab Mol Biol,Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China

[4] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Dept Anesthesiol, Shanghai 200127, Peoples R China

[5] Shanghai Jiao Tong Univ, Discipline Neurosci, Sch Med, Shanghai 200025, Peoples R China

[6] Shanghai Jiao Tong Univ, Sch Med, Dept Anat & Physiol, Shanghai 200025, Peoples R China

[7] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27514 USA

[8] Univ N Carolina, Sch Med, Neurosci Ctr, Chapel Hill, NC 27514 USA

[9] RIKEN, Brain Sci Inst, Res Resources Ctr, 2-1 Hirosawa, Wako, Saitama 3510198, Japan

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

中国国家自然科学基金;

关键词：

LINKED MENTAL-RETARDATION; CLEFT LIP/CLEFT PALATE; SYNAPTIC PLASTICITY; PROTEIN-SYNTHESIS; CELL-CYCLE; GENE; MUTATIONS; MEMORY; IDENTIFICATION; DIFFERENTIATION;

D O I：

10.1038/s41467-017-02531-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：11

共 43 条

[1]

A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate [J].