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.
Highlights
Transcription of eukaryotic genes ends with the recognition of a cleavage and poly-adenylation site in the genomic sequence that signals to the transcription machinery the “end” of the gene
We present here the hypothesis that a downstream effect of the reported abnormalities in calcium signaling in Autism Spectrum Disorder (ASD) individuals (Krey and Dolmetsch, 2007; Lu et al, 2012; Palmieri et al, 2010; Schmunk et al, 2015, 2017) would be the dysregulation of the mechanism of alternative poly-adenylation (APA)
Our hypothesis suggests that differential APA events are a downstream effect of some other dysregulated mechanism or possibly, a combination of such mechanisms. We suggest that these mechanisms might involve calcium signaling, as pathways controlled by calcium homeostasis are both known to be disrupted in ASD and be responsible for the regulation of transcriptional and post-transcriptional events
Summary
Transcription of eukaryotic genes ends with the recognition of a cleavage and poly-adenylation site in the genomic sequence that signals to the transcription machinery the “end” of the gene. The origin of the changes in the Pol II rate are different in the Fong et al (2014) study (mutations in the polymerase gene) and in our hypothesis (dysregulation of mechanisms such as calcium signaling), the end result is the same: detectable changes to APA Both the literature and existing transcriptomic data provide evidence supporting our model that links dysregulation of calcium homeostasis in the ASD brain with poly(A) site switching anomalies, mediated by calciumdependent signaling pathways controlling the speed and pausing of Pol II. Given the difficulty in predicting APA events from standard RNA-seq data, we suggest that the initial test of this hypothesis should focus on confirming dysregulation of the APA mechanism using a method that measures a signal from the actual polyadenylation site The majority of these methods work by capturing the poly-adenylation tail of transcript fragments, followed by sequencing a short segment of the nucleotides directly attached to it. The recent study by (Hollerer et al, 2016) suggesting increased usage of the distal poly(A) sites in cell lines as a general response to stress highlights the importance of exploring APA dysregulation in other disorders
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