Histone demethylase PHF2 activates CREB and promotes memory consolidation

Abstract

Long‐term memory formation is attributed to experience‐dependent gene expression. Dynamic changes in histone methylation are essential for the epigenetic regulation of memory consolidation‐related genes. Here, we demonstrate that the plant homeodomain finger protein 2 (PHF2) histone demethylase is upregulated in the mouse hippocampus during the experience phase and plays an essential role in memory formation. PHF2 promotes the expression of memory‐related genes by epigenetically reinforcing the TrkB–CREB signaling pathway. In behavioral tests, memory formation is enhanced by transgenic overexpression of PHF2 in mice, but is impaired by silencing PHF2 in the hippocampus. Electrophysiological studies reveal that PHF2 elevates field excitatory postsynaptic potential (fEPSP) and NMDA receptor‐mediated evoked excitatory postsynaptic current (EPSC) in CA1 pyramidal neurons, suggesting that PHF2 promotes long‐term potentiation. This study provides insight into the epigenetic regulation of learning and memory formation, which advances our knowledge to improve memory in patients with degenerative brain diseases.

Comorbid-phenome prediction and phenotype risk scores enhance gene discovery for generalized anxiety disorder and posttraumatic stress disorder

“…Some loci that positionally mapped (2-kb windows; 1-kb window on both sides to capture cis-regulatory effects) 19 to genic regions have prior evidence of involvement in GAD ( e . g ., PHF2 -rs12376738 and resistance to depression- and anxiety-like symptoms 20 and memory consolidation 21 ), PTSD ( e . g ., IL2 -rs45510091 and low dose cytokine treatments to reverse anxious symptoms), or related symptoms.…”

Kdm3b haploinsufficiency impairs the consolidation of cerebellum-dependent motor memory in mice

“…This result is interesting since we found that haploinsufficiency of Kdm3b impairs, rather than enhances, motor memory. A recent study showed that another H3K9 demethylase, plant homeodomain finger protein 2 (PHF2), acts as a positive regulator of hippocampal memory without affecting amygdala-dependent cued fear memory [ 47 ], suggesting that each histone demethylase may have a distinct role depending on brain regions and behavioral tasks. It would be interesting to examine the role of other histone-modifying enzymes, including LSD1, in cerebellar learning.…”

Positive correlations between social hierarchy and memory in weaning mice and young children

“…Identifying better memory in high-rank mice led us to investigate the expression levels of memory-related genes in the hippocampus, one of the crucial brain regions for memory consolidation and storage 47 . The results of quantitative PCR showed that the social ranks were negative corrected with the expression levels of GRIN2B (NR2B) 48 , a subunit of NMDA receptor that improves synaptic plasticity and memory in neurons, and Phf2, a histone demethylase (Figure 2A and B).…”

“…The negative correlation between ranks and Creb expression was also at the margin of statistical significance (Figure 2C). Phf2 and Creb have been reported to be involved in the TrkB-CREB signaling pathway for memory consolidation 47 . It is worth noting that other genes involved in this pathway, including Bdnf, Ntrk2 (TrkB), Cdk5, and Camk2, all showed decreasing trends with ranks, although the data is not statistically significant (Figure S3).…”

“…The TrkB-CREB signaling pathway has been implicated in hippocampal LTP 47 , which is critical for memory formation and memory consolidation 49 . To test whether augmented LTP caused the enhanced memory ability in mice with a higher social rank, we measured the field excitatory postsynaptic potentials (fEPSPs) on the dendritic fields of CA1 neurons and stimulated CA3 to CA1 Schaffer collaterals in acute hippocampal slices prepared from either 1 st -or 4 th -rank weanling mice (Figure 2D).…”