Tissue‐specific mechanisms of alternative polyadenylation: Testis, brain, and beyond (2018 update)

Abstract

Alternative polyadenylation (APA) is how genes choose different sites for 3′ end formation for mRNAs during transcription. APA often occurs in a tissue‐ or developmental stage‐specific manner that can significantly affect gene activity by changing the protein product generated, the stability of the transcript, its localization within the cell, or its translatability. Despite the important regulatory effects that APA has on tissue‐specific gene expression, only a few examples have been characterized mechanistically. In this 2018 update to our 2010 review, we examine mechanisms for the control of APA and update our understanding of the older mechanisms since 2010. We once postulated the existence of tissue‐specific factors in APA. However, while a few tissue‐specific polyadenylation factors are known, the emerging conclusion is that the majority of APA is accomplished by altering levels of core polyadenylation proteins. Examples of those core proteins include CSTF2, CPSF1, and subunits of mammalian cleavage factor I. But despite support for these mechanisms, no one has yet documented any of these proteins changing in either a tissue‐specific or developmental manner. Given the profound effect that APA can have on gene expression and human health, improved understanding of tissue‐specific APA could lead to numerous advances in gene activity control. This article is categorized under: RNA Processing > 3′ End Processing RNA in Disease and Development > RNA in Development

Pan‐tissue analysis of allelic alternative polyadenylation suggests widespread functional regulation

“…(ii) Specific trans ‐factors increasing the cleavage and polyadenylation accuracy of their target genes are co‐regulated with these genes in a tissue‐dependent manner. For example, genes with the major PAS located in the 3′UTR proximal (distal) to the stop codon could be more highly expressed in tissues with higher abundance of trans ‐factors favoring general 3′UTR shortening (lengthening; MacDonald & McMahon, ; MacDonald, ), or genes containing specific cis ‐regulatory sequences might be co‐regulated with the trans ‐factors targeting these cis ‐elements. This might result in increased polyadenylation error of genes in the tissues where the gene and its regulators both are lowly expressed.…”

A nuclear role for ARGONAUTE-2 in regulation of neuronal alternative polyadenylation

“…Alternative polyadenylation leads to the generation of 3ʹ mRNA variants (Di Giammartino et al, 2011;Elkon et al, 2013;Fu et al, 2018;Tian & Manley, 2017) that diversify the transcriptome expressed in the nervous system (Fontes et al, 2017;MacDonald, 2019;Miura et al, 2013;Ulitsky et al, 2012). APA contributes to differential mRNA localization (Mansfield & Keene, 2012;Taliaferro et al, 2016) and translation (Ainsley et al, 2014;Terenzio et al, 2018).…”

The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis

“…Both hnRNP H and F proteins are known to significantly contribute towards protein diversity by regulating mechanisms of alternative splicing and alternative polyadenylation with at least some level of functional redundancy [150,199]. Alternative polyadenylation involves the cleavage of alternative poly(A) sites on the 3′ end of pre-mRNA followed by the addition of an adenine nucleotide chain (100-250 residues long) to stabilise transcripts prior to translation [123]. All members of the hnRNP H/F family have been shown to interact with both intronic splicing enhancers and silencers with a bias towards G-triplet repeat binding sites [24].…”