Direct profiling of non-adenosines in poly(A) tails of endogenous and therapeutic mRNAs with Ninetails

Natalia Gumińska, Katarzyna Matylla-Kulińska, Paweł S. Krawczyk, Michał Maj, Wiktoria Orzeł, Zuzanna Mackiewicz, Aleksandra Brouze, Seweryn Mroczek and Andrzej Dziembowski ()
Additional contact information
Natalia Gumińska: International Institute of Molecular and Cell Biology
Katarzyna Matylla-Kulińska: International Institute of Molecular and Cell Biology
Paweł S. Krawczyk: International Institute of Molecular and Cell Biology
Michał Maj: NatWest Group
Wiktoria Orzeł: International Institute of Molecular and Cell Biology
Zuzanna Mackiewicz: International Institute of Molecular and Cell Biology
Aleksandra Brouze: International Institute of Molecular and Cell Biology
Seweryn Mroczek: International Institute of Molecular and Cell Biology
Andrzej Dziembowski: International Institute of Molecular and Cell Biology

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Stability and translation of mRNAs, both endogenous and therapeutic, is determined by poly(A) tail. Direct RNA sequencing enables single-molecule measurements of poly(A) lengths, avoiding amplification bias. It also holds potential for observation of non-adenosines within poly(A), known to influence mRNA fate. However, there is no computational method to detect composite tails in Direct Sequencing data. To address this gap, we introduce the Ninetails, a neural network-based tool that accurately identifies and quantifies non-adenosines in poly(A) tails. Examination of different biological contexts revealed widespread non-adenosine decorations, with frequencies influenced by the origin of poly(A) tails differing by mRNA class, cell type, and species. Notably, substrates of cytoplasmic TENT5-polymerases and mitochondrially encoded mRNAs are enriched in composite tails. For mRNA therapeutics, we show that the composition of poly(A) tails in mRNA vaccines is dynamic during its cellular lifetime and that the manufacturing protocol of synthetic mRNAs affects the purity of poly(A) tails.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-57787-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57787-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-57787-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().