Dataset Information

Systematic identification of 3'-UTR regulatory elements in activity-dependent mRNA stability in hippocampal neurons.

ABSTRACT: Ongoing neuronal activity during development and plasticity acts to refine synaptic connections and contributes to the induction of plasticity and ultimately long-term memory storage. Activity-dependent, post-transcriptional control of mRNAs occurs through transport to axonal and dendritic compartments, local translation and mRNA stability. We have identified a mechanism that contributes to activity-dependent regulation of mRNA stability during synaptic plasticity in rat hippocampal neurons. In this study, we demonstrate rapid, post-transcriptional control over process-enriched mRNAs by neuronal activity. Systematic analysis of the 3'-UTRs of destabilized transcripts, identifies enrichment in sequence motifs corresponding to microRNA (miRNA)-binding sites. The miRNAs that were identified, miR-326-3p/miR-330-5p, miR-485-5p, miR-666-3p and miR-761 are predicted to regulate networks of genes important in plasticity and development. We find that these miRNAs are developmentally regulated in the hippocampus, many increasing by postnatal day 14. We further find that miR-485-5p controls NGF-induced neurite outgrowth in PC12 cells, tau expression and axonal development in hippocampal neurons. miRNAs can function at the synapse to rapidly control and affect short- and long-term changes at the synapse. These processes likely occur during refinement of synaptic connections and contribute to the induction of plasticity and learning and memory.

SUBMITTER: Cohen JE

PROVIDER: S-EPMC4142030 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Systematic identification of 3'-UTR regulatory elements in activity-dependent mRNA stability in hippocampal neurons.

Cohen Jonathan E JE Lee Philip R PR Fields R Douglas RD

Philosophical transactions of the Royal Society of London. Series B, Biological sciences 20140901 1652

Ongoing neuronal activity during development and plasticity acts to refine synaptic connections and contributes to the induction of plasticity and ultimately long-term memory storage. Activity-dependent, post-transcriptional control of mRNAs occurs through transport to axonal and dendritic compartments, local translation and mRNA stability. We have identified a mechanism that contributes to activity-dependent regulation of mRNA stability during synaptic plasticity in rat hippocampal neurons. In ...[more]

PMID: 25135970

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Project description:Decoding post-transcriptional regulatory programs underlying gene expression is a crucial step toward a predictive dynamical understanding of cellular state transitions. Despite recent systematic efforts, the sequence determinants of such mechanisms remain largely uncharacterized. An important obstacle in revealing these elements stems from the contribution of local secondary structures in defining interaction partners in a variety of regulatory contexts, including but not limited to transcript stability, alternative splicing and localization. There are many documented instances where the presence of a structural regulatory element dictates alternative splicing patterns (e.g. human cardiac troponin T) or affects other aspects of RNA biology. Thus, a full characterization of post-transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence. We have developed a computational framework based on context-free grammars and mutual information that systematically explores the immense space of structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behavior. The application of this framework to genome-wide mammalian mRNA stability data revealed eight highly significant elements with substantial structural information, for the strongest of which we showed a major role in global mRNA regulation. Through biochemistry, mass-spectrometry, and in vivo binding studies, we identified HNRPA2B1 as the key regulator that binds this element and stabilizes a large number of its target genes. Ultimately, we created a global post-transcriptional regulatory map based on the identity of the discovered linear and structural cis-regulatory elements, their regulatory interactions and their target pathways. This approach can also be employed to reveal the structural elements that modulate other aspects of RNA behavior. This SuperSeries is composed of the following subset Series: GSE35749: sRSM1 synthetic decoy vs. scrambled transfections in MDA-MB-231 cells GSE35753: HNRPA2B1 RIP-chip GSE35756: Whole-genome decay rate measurements in MDA-MB-231 cells transfected with HNRPA2B1 siRNAs versus controls GSE35757: siRNA-mediated HNRPA2B1 knock-down in MDA-MB-231 cells GSE35799: HNRPA2B1 HITS-CLIP Refer to individual Series

Dataset Information

Systematic identification of 3'-UTR regulatory elements in activity-dependent mRNA stability in hippocampal neurons.

Publications

Systematic identification of 3'-UTR regulatory elements in activity-dependent mRNA stability in hippocampal neurons.

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