Mapping PTBP2 binding in human brain identifies SYNGAP1 as a target for therapeutic splice switching.
Mapping PTBP2 binding in human brain identifies SYNGAP1 as a target for therapeutic splice switching.
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DOI：
10.1038/s41467-023-38273-3
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发表时间：
2023-05-06
影响因子：
16.6
通讯作者：
Prosser, Benjamin L.
中科院分区：
文献类型：
--
作者：
Dawicki-McKenna, Jennine M.;Felix, Alex J.;Waxman, Elisa A.;Cheng, Congsheng;Amado, Defne A.;Ranum, Paul T.;Bogush, Alexey;Dungan, Lea V.;Maguire, Jean Ann;Gagne, Alyssa L.;Heller, Elizabeth A.;French, Deborah L.;Davidson, Beverly L.;Prosser, Benjamin L.
神经元基因的选择性剪接部分受多聚嘧啶束结合蛋白（PTBPs）的协调作用控制。虽然PTBP 1广泛表达，但PTBP 2主要是神经元的。在这里，我们使用脑组织和人诱导多能干细胞衍生的神经元（iPSC-神经元）来定义PTBP 2在人转录组中的足迹。我们映射PTBP 2结合位点，表征PTBP 2依赖的选择性剪接事件，并确定新的PTBP 2目标，包括SYNGAP 1，突触基因，其功能丧失导致复杂的神经发育障碍。我们发现PTBP 2与SYNGAP 1 mRNA的结合促进了选择性剪接和无义介导的衰变，并且破坏PTBP结合的反义寡核苷酸（ASO）重定向剪接并增加SYNGAP 1 mRNA和蛋白质表达。在SYNGAP 1单倍不足的iPSC神经元产生的两名患者，我们表明，PTBP 2靶向的ASO部分恢复SYNGAP 1的表达。我们的数据全面绘制了人类神经元和大脑皮层中PTBP 2依赖的选择性剪接，指导开发新的治疗工具，以造福神经发育障碍。Dawicki-McKenna和Felix等人全面绘制了人脑和神经元中PTBP 2的结合和选择性剪接图，从而确定了神经发育障碍相关基因SYNGAP 1的剪接转换治疗策略。
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. Dawicki-McKenna and Felix et al comprehensively map binding and alternative splicing by PTBP2 in human brain and neurons, thus identifying splice switching therapeutic strategies for the neurodevelopmental disorder associated gene SYNGAP1.
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