Editorial: Alternative Polyadenylation in Development and Disease.

Alternative polyadenylation, i.e., the production of mRNA isoforms with 3’ UTRs of different lengths or compositions depending on cell type, developmental stage, and the cell environment, has been shown to increase the astonishing complexity of gene regulation in eukaryotes. This Research Topic aimed to bring together contributions tackling the most pressing questions related to this phenomenon, namely the mechanisms behind this mode of regulation, its functional consequences, and the development of specific experimental and computational methods for its investigation. The contribution by Wei and Lai is concerned with the molecular mechanisms of APA. Their review focuses on the role of the conserved family of ELAV/Hu RNA-binding proteins in regulating APA, in particular by influencing the characteristic lengthening of 3’ UTR isoforms observed in neural tissues. The review also highlights the close connection between APA and alternative splicing, pointing to a crucial role of RNA-binding proteins in multiple aspects of gene regulation. The other contributions to the Topic focus on APA function from several complementary points of view. Experimental methods able to specifically investigate the functional consequences of APA are especially needed. In this Research Topic, Bae and Miura propose a CRISPR-based gene editing method for the deletion of long 3’ UTR isoforms in mouse embryonic stem cell-derived neurons, allowing a precise experimental assessment of the specific phenotypic consequences of APA. Their work also establishes embryonic stem cell-derived neurons as a convenient system for the study of post-transcriptional regulation in neural cells. A topic closely related to the functional relevance of APA is its evolutionary conservation. While APA has been studied in several model organisms, its existence and relevance in less studied species has yet to be elucidated. Scharfen et al. demonstrate the high prevalence of APA in an alga, Cyanidioschyzon merolae, highly diverged from yeast and animals. Notwithstanding the strong selective pressure experienced by this species to simplify its RNA-processing machinery, leading to widespread loss of introns and reduced splicing, APA occurs in a proportion of transcripts similar to that in animals. This observation strengthens the case for a fundamental and deeply conserved role of this regulatory modality to diversify the transcriptome. Methodologically, this contribution highlights the advantages of using modern high-throughput long-read sequencing techniques for the investigation of transcript structure and specifically of APA. An important role of APA is the regulation of mRNA stability and its subcellular localization. Guvenek et al. compared mRNA stability in different human cell lines. Specific transcripts, characterized by high GC content and more stable secondary structure, were shown to have higher stability in neuronal cells, and such cell type specificity extended to alternative isoforms generated by APA. This work suggests that the control of mRNA stability, including by APA, is a key factor in determining neuronal cell identity. Edited by: William C. Cho, QEH, Hong Kong SAR, China