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.
Highlights
Epigenomic abnormalities caused by genetic mutation in epigenetic regulators can result in neurodevelopmental disorders, deficiency in neural plasticity and mental retardation
The paired-pulse facilitation ratio was not altered by rapamycin in either control or mutant mice (Fig. 6e). These findings indicate that application of rapamycin can rescue the abnormal synaptic transmission and plasticity, suggesting that overactivation of mammalian target of rapamycin (mTOR) signaling pathway is involved in impaired learning/memory and synaptic potentiation
Our results reveal that histone demethylase PHF8 epigenetically represses the transcriptional activation of Ras- and RSK1encoding genes by demethylating H4K20me[1] at transcription start site (TSS) of target genes (Fig. 6f)
Summary
Epigenomic abnormalities caused by genetic mutation in epigenetic regulators can result in neurodevelopmental disorders, deficiency in neural plasticity and mental retardation. Our results indicate that loss of Phf[8] in animals causes deficient learning and memory by epigenetic disruption of mTOR signaling, and provides a potential therapeutic drug target to treat XLID. In vivo functional studies have revealed that loss of PHF8 causes apoptosis of neural cells in zebrafish and compromised locomotion in nematode, respectively[13,15]. Together, these studies provide evidence for the potential role of PHF8 in regulating cell differentiation and survival. The role of PHF8 in neural and cognitive function within mammalian brains remains unknown
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