NMD abnormalities during brain development in the Fmr1-knockout mouse model of fragile X syndrome

Kurosaki, Tatsuaki; Sakano, Hitomi; Pröschel, Christoph; Wheeler, Jason W.; Hewko, Alexander; Maquat, Lynne E.

doi:10.1186/s13059-021-02530-9

Cited by 12 publications

(17 citation statements)

References 61 publications

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“…Remarkably, the cerebellum was characterized by simultaneous up-regulation of NMD isoforms and down-regulation of expression in many genes, while in brain, blood, muscle and heart, the pattern was the opposite (Supplementary Figure S6). This finding suggests a special role for NMD in orchestrating cerebellar transcriptional programs ( 70 ) amid generally higher abundance of AS events and their contribution to the development of all these tissues ( 71–73 ).…”

Section: Resultsmentioning

confidence: 91%

Tissue-specific regulation of gene expression via unproductive splicing

Mironov

Petrova

Margasyuk

et al. 2023

Nucleic Acids Research

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Eukaryotic gene expression is regulated post-transcriptionally by a mechanism called unproductive splicing, in which mRNA is triggered to degrade by the nonsense-mediated decay (NMD) pathway as a result of regulated alternative splicing (AS). Only a few dozen unproductive splicing events (USEs) are currently documented, and many more remain to be identified. Here, we analyzed RNA-seq experiments from the Genotype-Tissue Expression (GTEx) Consortium to identify USEs, in which an increase in the NMD isoform splicing rate is accompanied by tissue-specific down-regulation of the host gene. To characterize RNA-binding proteins (RBPs) that regulate USEs, we superimposed these results with RBP footprinting data and experiments on the response of the transcriptome to the perturbation of expression of a large panel of RBPs. Concordant tissue-specific changes between the expression of RBP and USE splicing rate revealed a high-confidence regulatory network including 27 tissue-specific USEs with strong evidence of RBP binding. Among them, we found previously unknown PTBP1-controlled events in the DCLK2 and IQGAP1 genes, for which we confirmed the regulatory effect using small interfering RNA (siRNA) knockdown experiments in the A549 cell line. In sum, we present a transcriptomic pipeline that allows the identification of tissue-specific USEs, potentially many more than were reported here using stringent filters.

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Section: Resultsmentioning

confidence: 91%

Tissue-specific regulation of gene expression via unproductive splicing

Mironov

Petrova

Margasyuk

et al. 2023

Nucleic Acids Research

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“…Remarkably, cerebellum was characterized by simultaneous upregulation of NMD isoforms and downregulation of expression in many genes, while in brain, blood, muscle, and heart, the pattern was the contrary (Figure S6). This finding suggests a special role of NMD in orchestrating cerebellar transcriptional programs [70] amid generally higher abundance of AS events and their contribution to the development of all these tissues [71, 72, 73].…”

Section: Resultsmentioning

confidence: 99%

Tissue-specific regulation of gene expression via unproductive splicing

Mironov

Vlasenok

Margasyuk

et al. 2022

Preprint

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Eukaryotic gene expression is regulated post-transcriptionally by a universal mechanism called unproductive splicing, in which mRNA is triggered to degradation by the nonsense-mediated decay (NMD) pathway as a result of alternative splicing (AS). Only a few dozen unproductive splicing events (USEs) are documented, and many more remain to be identified. We performed an exhaustive search to catalog experimentally-validated and annotated USEs and monitored them in a panel of RNA-seq experiments from Genotype-Tissue Expression Consortium by detecting concordant tissue-specific changes of gene expression levels and NMD isoform splicing rates. A juxtaposition of these data with transcriptomic responses to RNA-binding protein (RBP) expression perturbations from ENCODE Consortium and RBP footprinting data revealed a number of remarkable cases of regulated USEs with strong tissue-specific signatures, including previously proposed models of brain-specific regulation of PTBP2, DLG4, and GABBR1 mediated by PTBP1. Additionally, we identified a high-confidence set of 86 novel AS events generating NMD isoforms that are associated with tissue-specific downregulation of gene expression. We present a gallery of novel predicted USEs, including a PTBP1-controlled event in the DCLK2 gene, which may be responsible for its inhibition in non-neural tissues. These results greatly expand current knowledge on tissue-specific unproductive splicing and its regulation.

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“…While UPF1 has been extensively studied in dividing cells, the precise role of UPF1-dependent mRNA decay in postmitotic neurons remains unresolved. It has been shown to enable compartmentalized gene expression, modulate synaptic activity and axon guidance, and regulate the expression of neuronal mRNAs that are critical for mouse brain development (Colak et al, 2013; Kurosaki et al, 2021b; Tan et al, 2020). Given the extent of defective mRNA metabolism in ALS, it is unsurprising that alterations in UPF1-mediated NMD activity have been highlighted in several studies.…”

Section: Introductionmentioning

confidence: 99%

ALS-Associated TDP-43 Dysfunction Compromises UPF1-Dependent mRNA Metabolism Pathways Including Alternative Polyadenylation and 3’UTR Length

Alessandrini,

Wright,

Kurosaki

et al. 2024

Preprint

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UPF1-mediated decay entails several mRNA surveillance pathways that play a crucial role in cellular homeostasis. However, the precise role of UPF1 in postmitotic neurons remains unresolved, as does its activity in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease characterized by TDP-43 pathology and disrupted mRNA metabolism. Here, we used human iPSC-derived spinal motor neurons (MNs) to identify mRNAs subject to UPF1 degradation by integrating RNA-seq before and after UPF1 knockdown with RIP-seq to identify RNAs that co-immunoprecipitate with the active form of phosphorylated UPF1. We define a stringent set of bona fide UPF1 targets in MNs that are functionally enriched for autophagy and structurally enriched for GC-rich and long 3' UTRs but not for premature termination codon (PTC)-containing transcripts. TDP-43 depletion in iPSC-derived MNs reduces UPF1 phosphorylation and consequently post-transcriptional upregulation of UPF1 targets, suggesting that TDP-43 dysfunction compromises UPF1-mediated mRNA surveillance. Intriguingly, our datasets reveal that UPF1 and TDP-43 regulate alternative polyadenylation and 3'UTR length of mRNAs associated with synaptic and axonal function, a process that we find to be compromised in ALS models in vitro and ALS patient tissue. Our study provides a comprehensive description of UPF1-mediated mRNA decay activity in neurons, reveals overlapping roles between UPF1 and TDP-43 in regulating 3'UTR length, and offers novel insight into the intricate interplay between RNA metabolism and neurodegeneration in ALS.

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NMD abnormalities during brain development in the Fmr1-knockout mouse model of fragile X syndrome

Cited by 12 publications

References 61 publications

Tissue-specific regulation of gene expression via unproductive splicing

Tissue-specific regulation of gene expression via unproductive splicing

Tissue-specific regulation of gene expression via unproductive splicing

ALS-Associated TDP-43 Dysfunction Compromises UPF1-Dependent mRNA Metabolism Pathways Including Alternative Polyadenylation and 3’UTR Length

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