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, Charlie Degui Chen

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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.

Original languageEnglish
Article number114
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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