Alternative splicing–triggered mRNA decay informs splice-switching targets for neurodevelopmental disorders
Kaining Hu, Runwei Yang, Jiaming Qiu, Xinran Feng, Kayleigh J. LaPre, Jessica Tanouye, Yalan Yang, Xiaochang Zhang
Kaining Hu, Runwei Yang, Jiaming Qiu, Xinran Feng, Kayleigh J. LaPre, Jessica Tanouye, Yalan Yang, Xiaochang Zhang
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Research Article Development Neuroscience

Alternative splicing–triggered mRNA decay informs splice-switching targets for neurodevelopmental disorders

Abstract

Alternative splicing–triggered nonsense-mediated mRNA decay (AS-NMD) critically regulates gene expression, but the extent to which neuronal genes are regulated by AS-NMD remains understudied. Here, we identified over 3,000 developmentally regulated AS-NMD exons in mouse and human brains and validated them in cultured neurons. AS-NMD suppresses synaptic genes during brain development and differentially regulates more than 200 causal genes for neurodevelopmental disorders (NDDs). We detected a poison exon in GRIA2 and identified splice-switching antisense oligonucleotides that suppressed GRIA2 NMD and increased its functional isoforms. In summary, this study uncovers genes repressed by AS-NMD in the brain and nominates amenable splice-switching targets for treating dominant NDDs such as autism spectrum disorders and developmental epileptic encephalopathy.

Authors

Kaining Hu, Runwei Yang, Jiaming Qiu, Xinran Feng, Kayleigh J. LaPre, Jessica Tanouye, Yalan Yang, Xiaochang Zhang

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Figure 5

Validation of AS-NMD exons in human iPSC-derived neurons.

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Validation of AS-NMD exons in human iPSC-derived neurons. (A) Human iPSC...
(A) Human iPSC-derived neurons (iNeurons) were treated with DMSO (n = 3 biological replicates) or CHX (n = 3) for splicing analyses. (B) A pie chart showing differentially spliced SEs and the fractions of predicted AS-NMD exons when iNeurons were treated with CHX. (C) Violin plot of PSI and TPM for EANMD-predicted human brain SEs with significantly changed SEs (FDR < 0.05, minimum NMD score > 0.132) in iNeurons (NMD_in, n = 175; NMD_ex, n = 321; ORF preserving, n = 145; ORF changing, n = 18; 1-way ANOVA followed by Tukey’s multiple-comparison test); 141 NMD_in and 302 NMD_ex events had expected changes in CHX-treated iNeurons. (D) DisGeNET enrichment analysis for haploinsufficient genes (pLI > 0.9) regulated by SE-NMD exons in the human brain. Solid dots indicate that AS-NMD exons were validated with RNA-seq and/or RT-PCR. (E) Sashimi plots showing validated NMD_in exons in FOXP1 and SNRPB (hg38). (F) Sashimi plot showing the NMD_ex exon in DLG4 had decreased PSI in CHX-treated iNeurons (hg38).