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 Phf21bdelta4/delta4) 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 (Phf21bdelta4/delta4) and controls (WT) were used for RNAseq experiments植物同源结构域（plant homeodomain, PHD）锌指蛋白是一类表观遗传读取因子，其功能异常与多种神经系统疾病相关，但PHD锌指蛋白缺失导致疾病的分子机制仍未阐明。本研究构建了敲除PHD锌指蛋白21B（PHD finger protein 21B, Phf21b）的CRISPR编辑小鼠模型Phf21b^Δ4/Δ4，以探究其在大脑中的生物学功能。基因敲除（knockout, KO）小鼠表现出社交记忆受损；在敲除小鼠的海马组织中，可观察到突触蛋白表达水平降低以及长时程增强（long-term potentiation, LTP）功能受损。转录组测序分析显示，参与突触可塑性过程的基因存在差异表达。进一步研究发现，PHF21B可与介导转录激活的组蛋白修饰——组蛋白H3赖氨酸36三甲基化（histone H3 tri-methylated lysine 36, H3K36me3）以及转录因子CREB发生全新的相互作用。上述研究结果证实，PHF21B是突触可塑性相关基因的重要上游调控因子，同时也是小鼠神经行为功能异常的潜在治疗靶点，有望应用于人类神经系统及精神疾病的诊疗。本研究采用Phf21b敲除CRISPR小鼠模型（Phf21b^Δ4/Δ4）及其野生型（wild type, WT）对照小鼠的海马组织开展RNA测序（RNA-seq）实验。