RETRACTED: Genomic Decoding of Neuronal Depolarization by Stimulus-Specific NPAS4 Heterodimers

Brigidi, G. Stefano; Hayes, Michael; Santos, Nathaniel Delos; Hartzell, Andrea L.; Texari, Lorane; Lin, Pei-Ann; Bartlett, Anna; Ecker, Joseph R.; Benner, Christopher; Heinz, Sven; Bloodgood, Brenda L.

doi:10.1016/j.cell.2019.09.004

Cited by 74 publications

(59 citation statements)

References 98 publications

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“…Advanced techniques, such as MCP-FP (MS2 bacteriophage coat protein-FP), λN-FP (N protein of bacteriophage λ-FP), RCas9-FP (dead RNA Cas9-FP), and fluorescent RNA aptamer system, have allowed visualization of RNA trafficking in live cells. Co-expression of a MCP-FP or λN-FP protein construct and a reporter construct containing phage protein binding motif sequence upstream of 3′ UTR of interest allowed tracking of mRNA localization in live cells [75,76]. Simultaneous delivery of RCas9-FP and target-specific single guide RNA allowed binding of the Cas9 to the mRNA of interest and visual tracking of endogenous mRNAs in live cells [77].…”

Section: Box 2 Experimental Approaches To Study Localization Of Mrnasmentioning

confidence: 99%

Emerging Roles for 3′ UTRs in Neurons

Bae

Miura

2020

IJMS

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The 3′ untranslated regions (3′ UTRs) of mRNAs serve as hubs for post-transcriptional control as the targets of microRNAs (miRNAs) and RNA-binding proteins (RBPs). Sequences in 3′ UTRs confer alterations in mRNA stability, direct mRNA localization to subcellular regions, and impart translational control. Thousands of mRNAs are localized to subcellular compartments in neurons—including axons, dendrites, and synapses—where they are thought to undergo local translation. Despite an established role for 3′ UTR sequences in imparting mRNA localization in neurons, the specific RNA sequences and structural features at play remain poorly understood. The nervous system selectively expresses longer 3′ UTR isoforms via alternative polyadenylation (APA). The regulation of APA in neurons and the neuronal functions of longer 3′ UTR mRNA isoforms are starting to be uncovered. Surprising roles for 3′ UTRs are emerging beyond the regulation of protein synthesis and include roles as RBP delivery scaffolds and regulators of alternative splicing. Evidence is also emerging that 3′ UTRs can be cleaved, leading to stable, isolated 3′ UTR fragments which are of unknown function. Mutations in 3′ UTRs are implicated in several neurological disorders—more studies are needed to uncover how these mutations impact gene regulation and what is their relationship to disease severity.

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Section: Box 2 Experimental Approaches To Study Localization Of Mrnasmentioning

confidence: 99%

Emerging Roles for 3′ UTRs in Neurons

Bae

Miura

2020

IJMS

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“…In this study, we implemented a proximity-ligation assay to systematically characterize changes in the nuclear proteome triggered by neuronal stimulation. While advances in transcriptomic technologies have enabled the identification of genes that undergo activitydependent changes in expression (Brigidi et al, 2019;Chen et al, 2017;Fernandez-Albert et al, 2019;Tyssowski et al, 2018), the systematic identification of proteins that undergo changes in subcellular localization and/or stability has been more challenging. Our results provide the first, to our knowledge, unbiased characterization of the population of proteins that undergo changes in nuclear abundance following neuronal silencing and/or glutamatergic stimulation, and does so in a manner that is independent of translation or transcription.…”

Section: Discussionmentioning

confidence: 99%

“…. While the activity-dependent transcriptome and translatome of neurons has been characterized using RNA sequencing (Brigidi et al, 2019;Hrvatin et al, 2018;Lacar et al, 2016;Tyssowski et al, 2018) and TRAP-seq (Chen et al, 2017;Fernandez-Albert et al, 2019), little work has been done to characterize the population of proteins that undergo activity-dependent changes in nuclear abundance due to regulated transport or stability. By inhibiting translation to exclude changes due to protein synthesis, the present study focused on identifying pre-existing proteins that undergo activitydependent changes in concentration in the nucleus via regulated nucleocytoplasmic trafficking and/or changes in stability.…”

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confidence: 99%

Neuronal activity promotes nuclear proteasome-mediated degradation of PDCD4 to regulate activity-dependent transcription

Deng

et al. 2021

Preprint

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Activity-dependent gene expression is critical for synapse development and plasticity. To elucidate novel mechanisms linking neuronal activity to changes in transcription, we compared the nuclear proteomes of tetrodotoxin-silenced and bicuculline-stimulated cultured rodent neurons using nuclear-localized APEX2 proximity biotinylation and mass spectrometry. The tumor suppressor protein PDCD4 was enriched in the silenced nuclear proteome, and PDCD4 levels rapidly decreased in the nucleus and cytoplasm of stimulated neurons. The activity-dependent decrease of PDCD4 was prevented by inhibitors of both PKC and proteasome activity and by a phospho-incompetent mutation of Ser71 in the βTRCP ubiquitin ligase-binding motif of PDCD4. We compared the activity-dependent transcriptomes of neurons expressing wildtype or degradation-resistant (S71A) PDCD4. We identified 91 genes as PDCD4 targets at the transcriptional level, including genes encoding proteins critical for synapse formation, remodeling, and transmission. Our findings indicate that regulated degradation of nuclear PDCD4 facilitates activity-dependent transcription in neurons.

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“…where a modified TF does not bind as well to its canonical motif. Here, de novo motif finding methods can recover the true binding motif, then MEIRLOP can determine enrichment of this motif, as performed in Bloodgood et al [59].…”

Section: Discussionmentioning

confidence: 99%

MEIRLOP: improving score-based motif enrichment by incorporating sequence bias covariates

2020

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Background Motif enrichment analysis (MEA) identifies over-represented transcription factor binding (TF) motifs in the DNA sequence of regulatory regions, enabling researchers to infer which transcription factors can regulate transcriptional response to a stimulus, or identify sequence features found near a target protein in a ChIP-seq experiment. Score-based MEA determines motifs enriched in regions exhibiting extreme differences in regulatory activity, but existing methods do not control for biases in GC content or dinucleotide composition. This lack of control for sequence bias, such as those often found in CpG islands, can obscure the enrichment of biologically relevant motifs. Results We developed Motif Enrichment In Ranked Lists of Peaks (MEIRLOP), a novel MEA method that determines enrichment of TF binding motifs in a list of scored regulatory regions, while controlling for sequence bias. In this study, we compare MEIRLOP against other MEA methods in identifying binding motifs found enriched in differentially active regulatory regions after interferon-beta stimulus, finding that using logistic regression and covariates improves the ability to call enrichment of ISGF3 binding motifs from differential acetylation ChIP-seq data compared to other methods. Our method achieves similar or better performance compared to other methods when quantifying the enrichment of TF binding motifs from ENCODE TF ChIP-seq datasets. We also demonstrate how MEIRLOP is broadly applicable to the analysis of numerous types of NGS assays and experimental designs. Conclusions Our results demonstrate the importance of controlling for sequence bias when accurately identifying enriched DNA sequence motifs using score-based MEA. MEIRLOP is available for download from https://github.com/npdeloss/meirlop under the MIT license.

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RETRACTED: Genomic Decoding of Neuronal Depolarization by Stimulus-Specific NPAS4 Heterodimers

Cited by 74 publications

References 98 publications

Emerging Roles for 3′ UTRs in Neurons

Emerging Roles for 3′ UTRs in Neurons

Neuronal activity promotes nuclear proteasome-mediated degradation of PDCD4 to regulate activity-dependent transcription

MEIRLOP: improving score-based motif enrichment by incorporating sequence bias covariates

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