CLIP and Massively Parallel Functional Analysis of CELF6 Reveal a Role in Destabilizing Synaptic Gene mRNAs through Interaction with 3′ UTR Elements

Rieger, Michael A.; King, Dana; Crosby, Haley; Liu, Yating; Cohen, Barak A.; Dougherty, Joseph D.

doi:10.1016/j.celrep.2020.108531

Cited by 16 publications

(15 citation statements)

References 68 publications

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“…On the other hand, there could be a more non-specific mechanism where a variety of RBPs have redundant roles and work in a larger ensemble. For example, the set of RBPs identified as enriched in the upregulated transcripts is remarkably similar to the motifs found in our recent study of Celf6 binding targets (Rieger et al, 2020), even though the actual transcripts are distinct. As Celf6 and related Celf proteins have a role in forming RNA granules for mRNA storage and/or decay, and these granules often contain numerous species of RBPs and mRNAs interacting non-specifically through phase separation mediated by disordered domains, this suggests that transcripts enriched in binding for this selection of proteins may be more likely sequestered into a common granule awaiting release and translation following neuronal activation.…”

Section: Discussionsupporting

confidence: 79%

Activity dependent translation in astrocytes dynamically alters the proteome of the perisynaptic astrocyte process

Sapkota

Kater

Sakers

et al. 2020

Preprint

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Gene expression requires two stepstranscription and translationwhich can be regulated independently to allow nuanced, localized, and rapid responses to cellular stimuli. Neurons are known to respond transcriptionally and translationally to bursts of brain activity, and a transcriptional response to this activation has also been recently characterized in astrocytes. However, the extent to which astrocytes respond translationally is unknown. We tested the hypothesis that astrocytes also have a programmed translational response by characterizing the change in transcript ribosome occupancy in astrocytes using Translating Ribosome Affinity Purification subsequent to a robust induction of neuronal activity in vivo via acute seizure. We identified a reproducible change in transcripts on astrocyte ribosomes, highlighted by a rapid decrease in housekeeping transcripts, such as ribosomal and mitochondrial components, and a rapid increase in transcripts related to cytoskeleton, motor activity, ion transport, and cell communication. This indicates a dynamic response, some of which might be secondary to activation of Receptor Tyrosine Kinase signaling. Using acute slices, we quantified the extent to which individual cues and sequela of neuronal activity can activate translation acutely in astrocytes. This identified both BDNF and KCl as contributors to translation induction, the latter with both action-potential sensitive and insensitive components. Finally, we show that this translational response requires the presence of neurons, indicating the response is acutely or chronically non-cell autonomous. Regulation of translation in astrocytes by neuronal activity suggests an additional mechanism by which astrocytes may dynamically modulate nervous system functioning.

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Section: Discussionsupporting

confidence: 79%

Activity dependent translation in astrocytes dynamically alters the proteome of the perisynaptic astrocyte process

Sapkota

Kater

Sakers

et al. 2020

Preprint

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“…CELF1 and CELF2 are extensively expressed in numerous tissues throughout the human body, but CELF3 through 5 are mostly found in the neurological system. CELF6 is most often found in the nervous system, the kidneys, and the testes [5,11,12]. All six members have a similar structure that includes three RRMs (RNA Recognition Motifs), two in the N-terminal and one in the C-terminal, as well as a divergent linker region that can improve RBP binding affinity through conformational variations.…”

Section: General Characteristics Of the Celf Protein Familymentioning

confidence: 99%

“…In the cytoplasm, CELF proteins are involved in mRNA stability, translation, alternative polyadenylation (APA), and pre-miRNA maturation [12,32,[34][35][36]. CELFs regulate mRNA stability across the genome, although only specific, well-studied events are discussed in this section.…”

Section: General Characteristics Of the Celf Protein Familymentioning

confidence: 99%

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CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis

Aghdam

Jave‐Suárez

2021

IJMS

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Post-transcriptional modifications to coding and non-coding RNAs are unquestionably a pivotal way in which human mRNA and protein diversity can influence the different phases of a transcript’s life cycle. CELF (CUGBP Elav-like family) proteins are RBPs (RNA-binding proteins) with pleiotropic capabilities in RNA processing. Their responsibilities extend from alternative splicing and transcript editing in the nucleus to mRNA stability, and translation into the cytoplasm. In this way, CELF family members have been connected to global alterations in cancer proliferation and invasion, leading to their identification as potential tumor suppressors or even oncogenes. Notably, genetic variants, alternative splicing, phosphorylation, acetylation, subcellular distribution, competition with other RBPs, and ultimately lncRNAs, miRNAs, and circRNAs all impact CELF regulation. Discoveries have emerged about the control of CELF functions, particularly via noncoding RNAs, and CELF proteins have been identified as competing, antagonizing, and regulating agents of noncoding RNA biogenesis. On the other hand, CELFs are an intriguing example through which to broaden our understanding of the RBP/noncoding RNA regulatory axis. Balancing these complex pathways in cancer is undeniably pivotal and deserves further research. This review outlines some mechanisms of CELF protein regulation and their functional consequences in cancer physiology.

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“…Following the completion of membrane transfer, the membrane was cut with a clean razor to obtain a vertical membrane slice per lane from 50 kDa (molecular weight of hnRNP H) to 75 kDa, which translates to 30 to 70 nucleotide RNA fragments crosslinked to the protein. RNA was then extracted from the membrane slices following a previously described procedure (Rieger et al, 2020). The same extraction procedure (starting with the addition of 7M urea) was used to isolate RNA from samples previously stored for total RNA-seq.…”

Section: Clip-seq and Total Rna-seq Library Preparationmentioning

confidence: 99%

Cacna2d2 is an hnRNP H target of the striatal mRNA targetome and regulates methamphetamine behavior

Ruan

Rieger²,

Lynch

et al. 2021

Preprint

Self Cite

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We previously identified Hnrnph1 (heterogeneous nuclear ribonucleoprotein H1) as a quantitative trait gene underlying reduced methamphetamine behavioral sensitivity. Mice with a heterozygous frameshift deletion in the first coding exon of Hnrnph1 showed reduced methamphetamine-induced dopamine release and behaviors. To inform the mechanism linking hnRNP H dysfunction with reduced methamphetamine-induced dopamine release and behavior, we surveyed the RNA targetome of hnRNP H via cross-linking immunoprecipitation coupled with RNA-sequencing in striatal tissue at baseline and at 30 min post-methamphetamine (2 mg/kg, i.p.). Methamphetamine induced opposite changes in RNA-binding targets of hnRNP H in Hnrnph1 mutants versus wild-types, including 3′UTR targets in mRNAs enriched for synaptic proteins involved in dopamine release and excitatory synaptic plasticity. Targetome, transcriptome, and spliceome analyses triangulated on a methamphetamine-induced upregulation of Cacna2d2 transcript and decreased 3′UTR usage in hyposensitive Hnrnph1 mutants. Our study identifies a dynamic methamphetamine-induced RNA targetome of hnRNP H that has the potential to rapidly regulate gene expression, synaptic transmission, plasticity, and behavior.

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CLIP and Massively Parallel Functional Analysis of CELF6 Reveal a Role in Destabilizing Synaptic Gene mRNAs through Interaction with 3′ UTR Elements

Cited by 16 publications

References 68 publications

Activity dependent translation in astrocytes dynamically alters the proteome of the perisynaptic astrocyte process

Activity dependent translation in astrocytes dynamically alters the proteome of the perisynaptic astrocyte process

CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis

Cacna2d2 is an hnRNP H target of the striatal mRNA targetome and regulates methamphetamine behavior

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