Mapping PTBP2 binding in human brain identifies SYNGAP1 as a target for therapeutic splice switching

Jennine M. Dawicki-McKenna, Alex J. Felix, Elisa A. Waxman, Congsheng Cheng, Defne A. Amado, Paul T. Ranum, Alexey Bogush, Lea V. Dungan, Jean Ann Maguire, Alyssa L. Gagne, Elizabeth A. Heller, Deborah L. French, Beverly L. Davidson () and Benjamin L. Prosser ()
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Jennine M. Dawicki-McKenna: University of Pennsylvania Perelman School of Medicine
Alex J. Felix: University of Pennsylvania Perelman School of Medicine
Elisa A. Waxman: University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia
Congsheng Cheng: Children’s Hospital of Philadelphia
Defne A. Amado: Children’s Hospital of Philadelphia
Paul T. Ranum: Children’s Hospital of Philadelphia
Alexey Bogush: University of Pennsylvania Perelman School of Medicine
Lea V. Dungan: University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia
Jean Ann Maguire: Children’s Hospital of Philadelphia
Alyssa L. Gagne: Children’s Hospital of Philadelphia
Elizabeth A. Heller: University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia
Deborah L. French: University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia
Beverly L. Davidson: University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia
Benjamin L. Prosser: University of Pennsylvania Perelman School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Alternative splicing of neuronal genes is controlled partly by the coordinated action of polypyrimidine tract binding proteins (PTBPs). While PTBP1 is ubiquitously expressed, PTBP2 is predominantly neuronal. Here, we define the PTBP2 footprint in the human transcriptome using brain tissue and human induced pluripotent stem cell-derived neurons (iPSC-neurons). We map PTBP2 binding sites, characterize PTBP2-dependent alternative splicing events, and identify novel PTBP2 targets including SYNGAP1, a synaptic gene whose loss-of-function leads to a complex neurodevelopmental disorder. We find that PTBP2 binding to SYNGAP1 mRNA promotes alternative splicing and nonsense-mediated decay, and that antisense oligonucleotides (ASOs) that disrupt PTBP binding redirect splicing and increase SYNGAP1 mRNA and protein expression. In SYNGAP1 haploinsufficient iPSC-neurons generated from two patients, we show that PTBP2-targeting ASOs partially restore SYNGAP1 expression. Our data comprehensively map PTBP2-dependent alternative splicing in human neurons and cerebral cortex, guiding development of novel therapeutic tools to benefit neurodevelopmental disorders.

Date: 2023
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DOI: 10.1038/s41467-023-38273-3

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