Molecular Regulation of Alternative Polyadenylation (APA) within the Drosophila Nervous System

Abstract

Alternative polyadenylation (APA) is a widespread gene regulatory mechanism that generates mRNAs with different 3′-ends, allowing them to interact with different sets of RNA regulators such as microRNAs and RNA-binding proteins. Recent studies have shown that during development, neural tissues produce mRNAs with particularly long 3′UTRs, suggesting that such extensions might be important for neural development and function. Despite this, the mechanisms underlying neural APA are not well understood. Here, we investigate this problem within the Drosophila nervous system, focusing on the roles played by general cleavage and polyadenylation factors (CPA factors). In particular, we examine the model that modulations in CPA factor concentration may affect APA during development. For this, we first analyse the expression of the Drosophila orthologues of all mammalian CPA factors and note that their expression decreases during embryogenesis. In contrast to this global developmental decrease in CPA factor expression, we see that cleavage factor I (CFI) expression is actually elevated in the late embryonic central nervous system, suggesting that CFI might play a special role in neural tissues. To test this, we use the UAS/Gal4 system to deplete CFI proteins from neural tissue and observe that in this condition, multiple genes switch their APA patterns, demonstrating a role of CFI in APA control during Drosophila neural development. Furthermore, analysis of genes with 3′UTR extensions of different length leads us to suggest a novel relation between 3′UTR length and sensitivity to CPA factor expression. Our work thus contributes to the understanding of the mechanisms of APA control within the developing central nervous system.

Regulation of ribosomal protein genes: An ordered anarchy

“…Like most eukaryotic genes, the 3′ UTRs of RPGs are longer and more heterogeneous in size than the 5′ UTRs. Alternative 3′ end formation and/or polyadenylation, which modify the position of the mRNA 3′ end, have been recorded for eukaryotic RPGs, including those in yeast and metazoan (Antione & Fried, 1995; Chakrabarti, Dinkins, & Hunt, 2018; Gudipati, Neil, Feuerbach, Malabat, & Jacquier, 2012; Parenteau et al, 2015; Stevens, Howe, & Hunt, 2018; Vallejos Baier, Picao‐Osorio, & Alonso, 2017). The relatively short size of RPGs 5′ UTRs may reflect the need for efficient translation, while the long and heterogeneous 3′ UTRs may provide opportunities for gene regulation.…”

Selective poly adenylation predicts the efficacy of immunotherapy in patients with lung adenocarcinoma by multiple omics research

“…In summary, eight model genes were used in the gene set for this analysis, and it was found that they were regulated by multiple transcription factors and other common mechanisms [37][38][39]. Transcription factor NFAT5 was the main regulator of gene concentration, and there was statistical significance in the difference of survival prognosis and immune cell infiltration in LUAD (P < 0.05).…”

A Developmental Mechanism to Regulate Alternative Polyadenylation in an Adult Stem Cell Lineage

“…Since transcripts from more than 70% of human genes are alterna7vely polyadenylated under one condi7on or another, APA is widespread (Gruber and Zavolan 2019). The most intriguing cases are those where the choice of 3' end cut site is developmentally regulated, leading, for example, to produc7on of transcripts with longer 3'UTRs from specific genes in neurons or shorter 3'UTRs in differen7a7ng male germ cells compared to precursor cells (Hilgers et al 2012;Miura et al 2013;Shan et al 2017;Vallejos Baier et al 2017;Grassi et al 2019;Berry et al 2022).…”

“…The site at which 3' end cleavage will take place is guided by recogni7on by CPSF through the components CPSF30 and WDR33 of the polyadenyla7on signal (PAS), an hexamer (most commonly AAUAAA or a close variant) in the nascent mRNA usually ~15-30 nucleo7des upstream of the cleavage site (Clerici et al 2018;Gallicchio et al 2023). While the central role of the core complex CPSF in recognizing the PAS and cleaving the nascent mRNA molecule is rela7vely clear, the specific contribu7ons of the other complexes and associated factors in specifying whether, where, on what specific gene products, and in which cell types a cut is made is under inves7ga7on (Vallejos Baier et al 2017;Zhu et al 2018;Turner et al 2020).…”