Genomic context tunes sequence-encoded RNA processing

Sequence and genomic position jointly determine RNA processing, but at native loci the two are difficult to separate. Here, we uncoupled them by integrating RNA-processing elements into endogenous transcription units at tens of thousands of mapped positions and different elements at shared positions. Genomic position dominated RNA production levels but differentially influenced RNA processing events. A cryptic polyadenylation site, used natively only upon U1 inhibition, was rarely used ectopically. In contrast, introns partially retained at their native loci remained so across thousands of ectopic positions, with a substantial fraction of transcripts reaching the cytoplasm unspliced. SON depletion reduced splicing of two such introns, preferentially near speckles. Chromatin state, GC content, and speckle proximity tuned this behavior without overriding it, and in opposite directions: speckle proximity improved the splicing of one intron and reduced that of another. Specialized introns are therefore portable modules carrying their own processing information.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-11-02
DOI
https://doi.org/10.64898/2026.10.29.762830
Primary Topic
RNA Research and Splicing
Type
preprint

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preprint

Genomic context tunes sequence-encoded RNA processing

Mathias Nielsen, Igor Ulitsky, Lidia Garkul, Artyom A. Tyukaev
2 links
bioRxiv (Cold Spring Harbor Laboratory)
RNA Research and Splicing
preprint

Genomic context tunes sequence-encoded RNA processing

Mathias Nielsen, Igor Ulitsky, Lidia Garkul, Artyom A. Tyukaev
preprint en

Abstract

Sequence and genomic position jointly determine RNA processing, but at native loci the two are difficult to separate. Here, we uncoupled them by integrating RNA-processing elements into endogenous transcription units at tens of thousands of mapped positions and different elements at shared positions. Genomic position dominated RNA production levels but differentially influenced RNA processing events. A cryptic polyadenylation site, used natively only upon U1 inhibition, was rarely used ectopically. In contrast, introns partially retained at their native loci remained so across thousands of ectopic positions, with a substantial fraction of transcripts reaching the cytoplasm unspliced. SON depletion reduced splicing of two such introns, preferentially near speckles. Chromatin state, GC content, and speckle proximity tuned this behavior without overriding it, and in opposite directions: speckle proximity improved the splicing of one intron and reduced that of another. Specialized introns are therefore portable modules carrying their own processing information.

bioRxiv (Cold Spring Harbor Laboratory)
Lomonosov Moscow State University (RU), Max Delbrück Center (DE), Weizmann Institute of Science (IL)
Novo Nordisk Fonden
RNA Research and Splicing
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