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Dysregulation of Alternative Poly-adenylation as a Potential Player in Autism Spectrum Disorder

Szkop, KJ; Cooke, PIC; Humphries, JA; Kalna, V; Moss, DS; Schuster, EF; Nobeli, I; (2017) Dysregulation of Alternative Poly-adenylation as a Potential Player in Autism Spectrum Disorder. Frontiers in Molecular Neuroscience , 10 , Article 279. 10.3389/fnmol.2017.00279. Green open access

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Abstract

We present here the hypothesis that alternative poly-adenylation (APA) is dysregulated in the brains of individuals affected by Autism Spectrum Disorder (ASD), due to disruptions in the calcium signaling networks. APA, the process of selecting different poly-adenylation sites on the same gene, yielding transcripts with different-length 3′ untranslated regions (UTRs), has been documented in different tissues, stages of development and pathologic conditions. Differential use of poly-adenylation sites has been shown to regulate the function, stability, localization and translation efficiency of target RNAs. However, the role of APA remains rather unexplored in neurodevelopmental conditions. In the human brain, where transcripts have the longest 3′ UTRs and are thus likely to be under more complex post-transcriptional regulation, erratic APA could be particularly detrimental. In the context of ASD, a condition that affects individuals in markedly different ways and whose symptoms exhibit a spectrum of severity, APA dysregulation could be amplified or dampened depending on the individual and the extent of the effect on specific genes would likely vary with genetic and environmental factors. If this hypothesis is correct, dysregulated APA events might be responsible for certain aspects of the phenotypes associated with ASD. Evidence supporting our hypothesis is derived from standard RNA-seq transcriptomic data but we suggest that future experiments should focus on techniques that probe the actual poly-adenylation site (3′ sequencing). To address issues arising from the use of post-mortem tissue and low numbers of heterogeneous samples affected by confounding factors (such as the age, gender and health of the individuals), carefully controlled in vitro systems will be required to model the effect of calcium signaling dysregulation in the ASD brain.

Type: Article
Title: Dysregulation of Alternative Poly-adenylation as a Potential Player in Autism Spectrum Disorder
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fnmol.2017.00279
Publisher version: https://doi.org/10.3389/fnmol.2017.00279
Language: English
Additional information: Copyright © 2017 Szkop, Cooke, Humphries, Kalna, Moss, Schuster and Nobeli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: autism spectrum disorder, alternative poly-adenylation, RNA–seq, calcium signaling, transcription
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10073453
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