Enhancers regulate 3′ end processing activity to control expression of alternative 3′UTR isoforms

Kwon, Buki; Fansler, Mervin M.; Patel, Neil D.; Lee, Jihye; Ma, Weirui; Mayr, Christine

doi:10.1038/s41467-022-30525-y

Cited by 28 publications

(24 citation statements)

References 109 publications

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“…We restricted our sequencing to explore CE alternative splicing, but there is likely a plethora of exon to 3’ end connectivity that await discovery with long read sequencing. For example, alternative promoter usage has been previously connected to alternative polyA site usage 54 , and enhancer activity/transcriptional activity has been shown to regulate APA 55, 56 . We identify several examples of such coordination here (Fig.…”

Section: Discussionmentioning

confidence: 99%

Coordination of Alternative Splicing and Alternative Polyadenylation revealed by Targeted Long-Read Sequencing

Zhang

Bae

Cuddleston

et al. 2023

Preprint

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Nervous system development is associated with extensive regulation of alternative splicing (AS) and alternative polyadenylation (APA). AS and APA have been extensively studied in isolation, but little is known about how these processes are coordinated. Here, the coordination of cassette exon (CE) splicing and APA in Drosophila was investigated using a targeted long-read sequencing approach we call Pull-a-Long-Seq (PL-Seq). This cost-effective method uses cDNA pulldown and Nanopore sequencing combined with an analysis pipeline to resolve the connectivity of alternative exons to alternative 3' ends. Using PL-Seq, we identified genes that exhibit significant differences in CE splicing depending on connectivity to short versus long 3'UTRs. Genomic long 3'UTR deletion was found to alter upstream CE splicing in short 3'UTR isoforms and ELAV loss differentially affected CE splicing depending on connectivity to alternative 3'UTRs. This work highlights the importance of considering connectivity to alternative 3'UTRs when monitoring AS events.

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Section: Discussionmentioning

confidence: 99%

Coordination of Alternative Splicing and Alternative Polyadenylation revealed by Targeted Long-Read Sequencing

Zhang

Bae

Cuddleston

et al. 2023

Preprint

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“…Another aspect that we approached in this study is the relationship between the enhancer function, based on histone PTMs and accessibility patterns, and AS events in A. gambiae . Previous evidence suggests that enhancers could mediate isoform-specific expression by regulating the production and binding of antisense transcripts, as well as by regulating messenger RNA 3′ end processing (Onodera et al, 2012, Shiau et al, 2021, Kwon et al, 2022). In such cases, enhancers were expected to be located intragenically, near the exons or introns that undergo AS (Lam and Hertel, 2002, Matlin, Clark and Smith, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Previous evidence suggests that enhancers could mediate isoform-specific expression by regulating the production and binding of antisense transcripts, as well as by regulating messenger RNA 3′ end processing (Onodera et al, 2012, Shiau et al, 2021, Kwon et al, 2022.…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing and its regulation in the malaria vectorAnopheles gambiae

Díaz-Terenti,

Gómez-Díaz

2023

Preprint

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Alternative splicing (AS) is a highly conserved mechanism that allows to expand the coding capacity of the genome by modifying how multiple isoforms are expressed or used to generate different phenotypes. Despite its importance in physiology and disease, genome-wide studies of AS are lacking in most insects, including mosquitoes. And, even for model organisms, chromatin associated processes involved in the regulation AS are poorly known. In this study, we investigated AS in the malaria mosquito Anopheles gambiae in the context tissue-specific gene expression and mosquito responses to a Plasmodium falciparum infection, as well as the relationship between patterns of differential isoform expression and usage with chromatin accessibility changes. For this, we combined RNA-seq and ATAC-seq data from A. gambiae midguts and salivary glands, and from infected and non-infected midguts. We report differences between tissues in the expression of 456 isoforms and in the use of 211 isoforms, highlighting the role of AS in tissue-specific gene expression regulation. Secondly, we find a clear and significant association between chromatin accessibility states and tissue-specific patterns of AS. The analysis of differential accessible regions located at splicing sites permitted the identification of several motifs resembling the binding sites of Drosophila TFs potentially involved in mosquito AS regulation. Finally, the genome-wide analysis of tissue-dependent enhancer activity revealed that approximately 20% of A. gambiae transcriptional enhancers annotate to a differentially expressed or used isoform and that their activation status is linked to AS differences between tissues. This research illuminates the role of AS in gene expression in vector mosquitoes, and identifies regulatory regions potentially involved in AS regulation, which could reveal novel strategies for vector control.

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“…have been implicated in the recruitment of specific components of the poly(A) machinery. Such recruitment may be further enhanced by transcription enhancers, via a variety of transcription factors and co-activators ( Kwon et al, 2022 ). These processes may also be modulated by various epigenetic mechanisms ( Kaczmarek Michaels et al, 2020 ; Lin et al, 2020 ; Nanavaty et al, 2020 ; Soles and Shi, 2021 ; Wood et al, 2008 ).…”

Section: Co- and Post-transcriptional Regulation Of Apamentioning

confidence: 99%

Sequential Polyadenylation to Enable Alternative mRNA 3’ End Formation

Cai

Liu

Zhang

et al. 2023

Molecules and Cells

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In eukaryotic cells, a key RNA processing step to generate mature mRNA is the coupled reaction for cleavage and polyadenylation (CPA) at the 3′ end of individual transcripts. Many transcripts are alternatively polyadenylated (APA) to produce mRNAs with different 3′ ends that may either alter protein coding sequence (CDS-APA) or create different lengths of 3′UTR (tandem-APA). As the CPA reaction is intimately associated with transcriptional termination, it has been widely assumed that APA is regulated co-transcriptionally. Isoforms terminated at different regions may have distinct RNA stability under different conditions, thus altering the ratio of APA isoforms. Such differential impacts on different isoforms have been considered as post-transcriptional APA, but strictly speaking, this can only be considered “apparent” APA, as the choice is not made during the CPA reaction. Interestingly, a recent study reveals sequential APA as a new mechanism for post-transcriptional APA. This minireview will focus on this new mechanism to provide insights into various documented regulatory paradigms.

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Enhancers regulate 3′ end processing activity to control expression of alternative 3′UTR isoforms

Cited by 28 publications

References 109 publications

Coordination of Alternative Splicing and Alternative Polyadenylation revealed by Targeted Long-Read Sequencing

Coordination of Alternative Splicing and Alternative Polyadenylation revealed by Targeted Long-Read Sequencing

Alternative splicing and its regulation in the malaria vectorAnopheles gambiae

Sequential Polyadenylation to Enable Alternative mRNA 3’ End Formation

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