TY - JOUR
T1 - The epigenetic reader PHF21B modulates murine social memory and synaptic plasticity–related genes
AU - Chin, Eunice W.M.
AU - Ma, Qi
AU - Ruan, Hongyu
AU - Chin, Camille
AU - Somasundaram, Aditya
AU - Zhang, Chunling
AU - Liu, Chunyu
AU - Lewis, Martin D.
AU - White, Melissa
AU - Smith, Tracey L.
AU - Battersby, Malcolm
AU - Yao, Wei Dong
AU - Lu, Xin Yun
AU - Arap, Wadih
AU - Licinio, Julio
AU - Wong, Ma Li
PY - 2022/7/22
Y1 - 2022/7/22
N2 - 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.
AB - 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.
KW - Synaptic dysfunction
KW - synaptic processes
KW - PHF21B
KW - Plant homeodomain (PHD) finger proteins
KW - murine social memory
KW - synaptic plasticity
KW - PHD protein deficits
KW - CRISPR mouse model
UR - http://www.scopus.com/inward/record.url?scp=85134791791&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/105193
UR - http://purl.org/au-research/grants/NHMRC/1145770
U2 - 10.1172/jci.insight.158081
DO - 10.1172/jci.insight.158081
M3 - Article
C2 - 35866480
AN - SCOPUS:85134791791
VL - 7
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 14
M1 - e158081
ER -