The epigenetic reader PHF21B modulates social memory and synaptic plasticity-related genes in mice

Plant homeodomain (PHD) finger proteins are epigenetic readers whose dysfunctions are implicated in neurological conditions, but the molecular mechanisms linking PHD protein deficits to disease remain unclear. Here we generated a PHD finger protein 21B (Phf21b)-depleted mutant CRISPR mouse model (Phf21bΔ4/Δ4) to examine its roles in the brain. KO animals exhibited impaired social memory. Reduced expression of synaptic proteins and impaired long-term potentiation were observed in the KO hippocampi. Transcriptome profiling revealed differential expression of genes involved in synaptic plasticity processes. Furthermore, we characterized a novel interaction of PHF21B to H3K36me3 (histone H3 tri-methylated lysine 36), a histone modification associated with transcriptional activation, and the transcriptional factor CREB. These results establish PHF21B as an important upstream regulator of synaptic plasticity-related genes, and a candidate therapeutic target for murine neurobehavioral dysfunction, with potential applications in human neurological and psychiatric disorders. Hippocampal tissues of Phf21b-depleted mutant CRISPR mouse model (Phf21bΔ4/Δ4) and controls (WT) were used for RNAseq experiments