Phf8 histone demethylase deficiency causes cognitive impairments through the mTOR pathway

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.

Hyperactive and anxiolytic‐like behaviors result from loss of COUP‐TFI/Nr2f1 in the mouse cortex

“…Our previous data showed a functional link between induction of the immediate early gene Egr1 and expression of COUP‐TFI in olfactory bulb interneuron maturation . Interestingly, deletion or reduction of the transcriptional co‐repressor Lysine‐Specific Demethylase 1 (LSD1) translates into decreased levels of activating histone marks at the Egr1 promoter and leads to behavioral deficits, and Phf8 histone demethylase deficiency results in hyperactivity in open field chambers . Since reduced levels of LSD1 or COUP‐TFI, both acting on the induction of Egr1, induce a low‐anxiety phenotype in mice, and both are implicated in hippocampus‐dependent learning and memory, we speculate that abnormal levels of Egr1 could be one of the factor responsible for the reduced anxiety levels observed in COUP‐TFI mutant mice.…”

The Emerging Role of ATP-Dependent Chromatin Remodeling in Memory and Substance Use Disorders

“…Inhibiting histone demethylation by blocking KDM1a enhances fear conditioning memory [35]. Whereas, KDM1A loss-of-function and Phf8 genetic deletion have been demonstrated to induce deficits in long-term memory formation and learning in the hippocampus and amygdala [36][37][38]. These non-linear results emphasize the complex role of histone methylation in regulating gene expression; some histone methylation marks have been shown to be critical for gene activation (such as H3K4, H3K48, and H3K79), whereas, other methylation marks are thought to be essential for gene inactivation (such as H3K9 and H3K27; see Table 1).…”

Histone 4 Lysine 20 Methylation: A Case for Neurodevelopmental Disease

“…Mice deficient in Phf8 (on a mixed 129/B6 background) show no gross developmental defects or cognitive defects but show resiliency to stress-induced anxiety and depression-like behaviors through the regulation of serotonin receptors in the prefrontal cortex [53]. In another Phf8 knockout mouse model (C57BL6/J backcross, N5), animals were found to have learning and memory impairments, compromised long-term potentiation, and increased basal synaptic transmission in the hippocampus [54]. Data suggest that Phf8 is involved in the suppression of mTOR signaling [54], a key pathway in both normal and abnormal development (i.e., cancer).…”

“…In another Phf8 knockout mouse model (C57BL6/J backcross, N5), animals were found to have learning and memory impairments, compromised long-term potentiation, and increased basal synaptic transmission in the hippocampus [54]. Data suggest that Phf8 is involved in the suppression of mTOR signaling [54], a key pathway in both normal and abnormal development (i.e., cancer). Moreover, differences between Phf8 knockout mouse models highlight the importance of controlling both the genetic background and the environment in epigenetic studies of development.…”