Neuronal activity regulates the nuclear proteome to promote activity-dependent transcription

The formation and plasticity of neuronal circuits relies on dynamic activity-dependent gene expression. Although recent work has revealed the identity of important transcriptional regulators and of genes that are transcribed and translated in response to activity, relatively little is known about the cell biological mechanisms by which activity alters the nuclear proteome of neurons to link neuronal stimulation to transcription. Using nucleus-specific proteomic mapping in silenced and stimulated neurons, we uncovered an understudied mechanism of nuclear proteome regulation: activity-dependent proteasome-mediated degradation. We found that the tumor suppressor protein PDCD4 undergoes rapid stimulus-induced degradation in the nucleus of neurons. We demonstrate that degradation of PDCD4 is required for normal activity-dependent transcription and that PDCD4 target genes include those encoding proteins critical for synapse formation, remodeling, and transmission. Our findings highlight the importance of the nuclear proteasome in regulating the activity-dependent nuclear proteome and point to a specific role for PDCD4 as a regulator of activity-dependent transcription in neurons.

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

10.1101/2021.02.06.429040 ◽

2021 ◽

Author(s):

Wendy A. Herbst ◽

Weixian Deng ◽

James A. Wohlschlegel ◽

Jennifer M. Achiro ◽

Kelsey C. Martin

Keyword(s):

Gene Expression ◽

Neuronal Activity ◽

Ubiquitin Ligase ◽

Synapse Formation ◽

Tumor Suppressor Protein ◽

Binding Motif ◽

Transcriptional Level ◽

Genes Encoding ◽

Nuclear Proteome ◽

Activity Dependent

AbstractActivity-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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MicroRNAs in central nervous system disorders: current advances in pathogenesis and treatment

The Egyptian Journal of Neurology Psychiatry and Neurosurgery ◽

10.1186/s41983-021-00289-1 ◽

2021 ◽

Vol 57 (1) ◽

Author(s):

Mona Hussein ◽

Rehab Magdy

Keyword(s):

Neurological Disorders ◽

Target Genes ◽

Transcriptional Regulators ◽

Therapeutic Strategies ◽

Regulatory Rna ◽

Altered Expression ◽

Rna Molecules ◽

Central Nervous System Disorders ◽

Novel Targets ◽

Lateral Sclerosis

AbstractMicroRNAs (miRNAs) are a class of short, non-coding, regulatory RNA molecules that function as post transcriptional regulators of gene expression. Altered expression of multiple miRNAs was found to be extensively involved in the pathogenesis of different neurological disorders including Alzheimer’s disease, Parkinson’s disease, stroke, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington’s disease. miRNAs are implicated in the pathogenesis of excitotoxicity, apoptosis, oxidative stress, inflammation, neurogenesis, angiogenesis, and blood–brain barrier protection. Consequently, miRNAs can serve as biomarkers for different neurological disorders. In recent years, advances in the miRNA field led to identification of potentially novel prospects in the development of new therapies for incurable CNS disorders. MiRNA-based therapeutics include miRNA mimics and inhibitors that can decrease or increase the expression of target genes. Better understanding of the mechanisms by which miRNAs are implicated in the pathogenesis of neurological disorders may provide novel targets to researchers for innovative therapeutic strategies.

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Dynamical Analysis of bantam-Regulated Drosophila Circadian Rhythm Model

International Journal of Bifurcation and Chaos ◽

10.1142/s0218127414501612 ◽

2014 ◽

Vol 24 (12) ◽

pp. 1450161 ◽

Cited By ~ 1

Author(s):

Ying Li ◽

Zengrong Liu

Keyword(s):

Circadian Rhythm ◽

Crucial Role ◽

Target Genes ◽

Classical Model ◽

Dynamical Analysis ◽

Biological Processes ◽

Biological Mechanisms ◽

Environmental Perturbations ◽

Dynamical Behaviors ◽

Important Regulator

MicroRNAs (miRNAs) interact with 3′untranslated region (UTR) elements of target genes to regulate mRNA stability or translation, and play a crucial role in regulating many different biological processes. bantam, a conserved miRNA, is involved in several functions, such as regulating Drosophila growth and circadian rhythm. Recently, it has been discovered that bantam plays a crucial role in the core circadian pacemaker. In this paper, based on experimental observations, a detailed dynamical model of bantam-regulated circadian clock system is developed to show the post-transcriptional behaviors in the modulation of Drosophila circadian rhythm, in which the regulation of bantam is incorporated into a classical model. The dynamical behaviors of the model are consistent with the experimental observations, which shows that bantam is an important regulator of Drosophila circadian rhythm. The sensitivity analysis of parameters demonstrates that with the regulation of bantam the system is more sensitive to perturbations, indicating that bantam regulation makes it easier for the organism to modulate its period against the environmental perturbations. The effectiveness in rescuing locomotor activity rhythms of mutated flies shows that bantam is necessary for strong and sustained rhythms. In addition, the biological mechanisms of bantam regulation are analyzed, which may help us more clearly understand Drosophila circadian rhythm regulated by other miRNAs.

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Syncrip/hnRNP Q is required for activity-induced Msp300/Nesprin-1 expression and new synapse formation

The Journal of Cell Biology ◽

10.1083/jcb.201903135 ◽

2020 ◽

Vol 219 (3) ◽

Cited By ~ 4

Author(s):

Joshua Titlow ◽

Francesca Robertson ◽

Aino Järvelin ◽

David Ish-Horowicz ◽

Carlas Smith ◽

...

Keyword(s):

Single Molecule ◽

Posttranscriptional Regulation ◽

Rna Binding ◽

Synapse Formation ◽

Long Distance ◽

Key Factor ◽

Larval Neuromuscular Junction ◽

Rnp Granules ◽

Activity Dependent

Memory and learning involve activity-driven expression of proteins and cytoskeletal reorganization at new synapses, requiring posttranscriptional regulation of localized mRNA a long distance from corresponding nuclei. A key factor expressed early in synapse formation is Msp300/Nesprin-1, which organizes actin filaments around the new synapse. How Msp300 expression is regulated during synaptic plasticity is poorly understood. Here, we show that activity-dependent accumulation of Msp300 in the postsynaptic compartment of the Drosophila larval neuromuscular junction is regulated by the conserved RNA binding protein Syncrip/hnRNP Q. Syncrip (Syp) binds to msp300 transcripts and is essential for plasticity. Single-molecule imaging shows that msp300 is associated with Syp in vivo and forms ribosome-rich granules that contain the translation factor eIF4E. Elevated neural activity alters the dynamics of Syp and the number of msp300:Syp:eIF4E RNP granules at the synapse, suggesting that these particles facilitate translation. These results introduce Syp as an important early acting activity-dependent regulator of a plasticity gene that is strongly associated with human ataxias.

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Transcriptional regulatory network analysis of developing human erythroid progenitors reveals patterns of coregulation and potential transcriptional regulators

Physiological Genomics ◽

10.1152/physiolgenomics.00055.2006 ◽

2006 ◽

Vol 28 (1) ◽

pp. 114-128 ◽

Cited By ~ 37

Author(s):

M. A. Keller ◽

S. Addya ◽

R. Vadigepalli ◽

B. Banini ◽

K. Delgrosso ◽

...

Keyword(s):

Network Analysis ◽

Blood Cell ◽

Regulatory Network ◽

Target Genes ◽

Transcriptional Regulatory Network ◽

Expression Patterns ◽

Transcriptional Regulators ◽

Erythroid Progenitors ◽

Hematopoietic Stem ◽

Transcriptional Regulatory

Deciphering the molecular basis for human erythropoiesis should yield information benefiting studies of the hemoglobinopathies and other erythroid disorders. We used an in vitro erythroid differentiation system to study the developing red blood cell transcriptome derived from adult CD34+ hematopoietic progenitor cells. mRNA expression profiling was used to characterize developing erythroid cells at six time points during differentiation ( days 1, 3, 5, 7, 9, and 11). Eleven thousand seven hundred sixty-three genes (20,963 Affymetrix probe sets) were expressed on day 1, and 1,504 genes, represented by 1,953 probe sets, were differentially expressed (DE) with 537 upregulated and 969 downregulated. A subset of the DE genes was validated using real-time RT-PCR. The DE probe sets were subjected to a cluster metric and could be divided into two, three, four, five, or six clusters of genes with different expression patterns in each cluster. Genes in these clusters were examined for shared transcription factor binding sites (TFBS) in their promoters by comparing enrichment of each TFBS relative to a reference set using transcriptional regulatory network analysis. The sets of TFBS enriched in genes up- and downregulated during erythropoiesis were distinct. This analysis identified transcriptional regulators critical to erythroid development, factors recently found to play a role, as well as a new list of potential candidates, including Evi-1, a potential silencer of genes upregulated during erythropoiesis. Thus this transcriptional regulatory network analysis has yielded a focused set of factors and their target genes whose role in differentiation of the hematopoietic stem cell into distinct blood cell lineages can be elucidated.

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Supraphysiological Concentrations of Bisphenol A Alter the Expression of Extracellular Vesicle-Enriched miRNAs From Human Primary Granulosa Cells

Toxicological Sciences ◽

10.1093/toxsci/kfz020 ◽

2019 ◽

Vol 169 (1) ◽

pp. 5-13 ◽

Cited By ~ 4

Author(s):

Rodosthenis S Rodosthenous ◽

Andrea A Baccarelli ◽

Abdallah Mansour ◽

Michal Adir ◽

Ariel Israel ◽

...

Keyword(s):

Bisphenol A ◽

Granulosa Cells ◽

Target Genes ◽

Quantitative Polymerase Chain Reaction ◽

Extracellular Vesicle ◽

Biological Mechanisms ◽

Expression Levels ◽

Biologically Relevant ◽

Reproductive Effects ◽

Polymerase Chain

Abstract Bisphenol A (BPA) is a widely used chemical that has been detected in follicular fluid and associated with adverse reproductive effects. Granulosa cells have an important role in follicular growth and oocyte maturation, however, little is known about the biological mechanisms of BPA toxicity on human granulosa cells. In this study, we exposed primary granulosa cells to different concentrations of BPA (0, 20, 200, 2000, and 20 000 ng/ml) and used quantitative polymerase chain reaction to measure the expression levels of miRNAs enriched in extracellular vesicles (EV-enriched miRNAs), and cellular levels of selected target genes of differentially expressed EV-enriched miRNAs. We found that exposure to 20 000 ng/ml BPA was associated with decreased levels of EV-miR-27b-3p (FC = 0.58, p = .04) and increased levels of its biologically relevant target genes FADD (FC = 1.22, p = .01), IGF1 (FC = 1.59, p = .06), and PPARG (FC = 1.73, p = .001) as compared with the control. In addition, we observed that under the same exposure conditions, the expression levels of miR-27b-3p in granulosa cells were also downregulated (FC = 0.65, p = .03) as compared with the control. Our findings suggest that both cellular and extracellular changes in gene expression may mediate BPA toxicity in granulosa cells.

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MicroRNAs in endometriosis: biological function and emerging biomarker candidates†

Biology of Reproduction ◽

10.1093/biolre/ioz014 ◽

2019 ◽

Vol 101 (6) ◽

pp. 1167-1178 ◽

Cited By ~ 6

Author(s):

Sarah Bjorkman ◽

Hugh S Taylor

Keyword(s):

Noncoding Rna ◽

Target Genes ◽

Biological Function ◽

Transcriptional Regulators ◽

Circulating Mirnas ◽

Common Chronic Disease ◽

Rna Molecules ◽

Small Noncoding Rna ◽

Reproductive Aged Women ◽

Delayed Time

AbstractMicroRNAs (miRNAs), a class of small noncoding RNA molecules, have been recognized as key post-transcriptional regulators associated with a multitude of human diseases. Global expression profiling studies have uncovered hundreds of miRNAs that are dysregulated in several diseases, and yielded many candidate biomarkers. This review will focus on miRNAs in endometriosis, a common chronic disease affecting nearly 10% of reproductive-aged women, which can cause pelvic pain, infertility, and a myriad of other symptoms. Endometriosis has delayed time to diagnosis when compared to other chronic diseases, as there is no current accurate, easily accessible, and noninvasive tool for diagnosis. Specific miRNAs have been identified as potential biomarkers for this disease in multiple studies. These and other miRNAs have been linked to target genes and functional pathways in disease-specific pathophysiology. Highlighting investigations into the roles of tissue and circulating miRNAs in endometriosis, published through June 2018, this review summarizes new connections between miRNA expression and the pathophysiology of endometriosis, including impacts on fertility. Future applications of miRNA biomarkers for precision medicine in diagnosing and managing endometriosis treatment are also discussed.

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