The epigenetic reader PHF21B modulates murine social memory and synaptic plasticity–related genes

Eunice W.M. Chin, Qi Ma, Hongyu Ruan, Camille Chin, Aditya Somasundaram, Chunling Zhang, Chunyu Liu, Martin D. Lewis, Melissa White, Tracey L. Smith, Malcolm Battersby, Wei Dong Yao, Xin Yun Lu, Wadih Arap, Julio Licinio, Ma Li Wong

Research output: Contribution to journalArticlepeer-review

Abstract

Synaptic dysfunction is a manifestation of several neurobehavioral and neurological disorders. A major therapeutic challenge lies in uncovering the upstream regulatory factors controlling synaptic processes. Plant homeodomain (PHD) finger proteins are epigenetic readers whose dysfunctions are implicated in neurological disorders. However, the molecular mechanisms linking PHD protein deficits to disease remain unclear. Here, we generated a PHD finger protein 21B–depleted (Phf21bdepleted) mutant CRISPR mouse model (hereafter called Phf21bΔ4/Δ4) to examine Phf21b’s roles in the brain. Phf21bΔ4/Δ4 animals exhibited impaired social memory. In addition, reduced expression of synaptic proteins and impaired long-term potentiation were observed in the Phf21bΔ4/Δ4 hippocampi. Transcriptome profiling revealed differential expression of genes involved in synaptic plasticity processes. Furthermore, we characterized a potentially novel interaction of PHF21B with histone H3 trimethylated lysine 36 (H3K36me3), 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 neurobehavioral dysfunction in mice, with potential applications in human neurological and psychiatric disorders.

Original languageEnglish (US)
Article numbere158081
JournalJCI Insight
Volume7
Issue number14
DOIs
StatePublished - Jul 22 2022

ASJC Scopus subject areas

  • Medicine(all)

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