Co-transcriptional splicing is delayed in the highly expressed thyroglobulin gene

TL;DR

This study shows that splicing of introns in the highly expressed thyroglobulin gene is delayed due to its high transcription rate and long transcription loops.

Contribution

The study reveals a splicing delay in the thyroglobulin gene caused by high transcription rates and long introns.

Findings

Splicing is delayed several tens of kilobases downstream of transcribed introns in the Tg gene.

High transcriptional rate may cause localized splicing factor deficiency, leading to delayed spliceosome assembly.

Long Tg introns are spliced promptly, unlike short introns, suggesting intron length affects splicing speed.

Abstract

Transcription of the majority of eukaryotic genes is accompanied by splicing. The timing of splicing varies significantly between introns, transcripts, genes and species. Although quick co-transcriptional intron removal has been demonstrated for many mammalian genes, most splicing events do not occur immediately after intron synthesis. In this study, we utilized the highly expressed Tg gene, which forms exceptionally long transcription loops, providing a convenient model for studying splicing dynamics using advanced light microscopy. Using single-cell oligopainting, we observed a splicing delay occurring several tens of kilobases downstream of a transcribed intron, a finding supported by standard cell population analyses. We speculate that this phenomenon is due to the abnormally high transcriptional rate of the Tg gene, which might lead to a localized deficiency in splicing factors and, consequently, delayed spliceosome assembly on thousands of nascent transcripts decorating the gene. Additionally, we found that, in contrast to what is seen for short introns (<10 kb), the long Tg intron (>50 kb) is spliced promptly, providing further support for the idea that intron length might modulate splicing speed.

Highlighted Article:
Using the greatly upregulated thyroglobulin gene as a model, this study demonstrates that, in highly expressed genes, intron splicing might be delayed for several tens of kilobases.

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