Sites of transcription initiation drive mRNA isoform selection

Alfonso-Gonzalez, Carlos; Legnini, Ivano; Holec, Sarah; Arrigoni, Laura; Ozbulut, Hasan Can; Mateos, Fernando; Koppstein, David; Rybak-Wolf, Agnieszka; Bönisch, Ulrike; Rajewsky, Nikolaus; Hilgers, Valérie

doi:10.1016/j.cell.2023.04.012

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Sites of transcription initiation drive mRNA isoform selection

MPS-Authors

Alfonso-Gonzalez, Carlos
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Holec, Sarah
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Arrigoni, Laura
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Ozbulut, Hasan Can
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Mateos, Fernando
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Koppstein, David
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Bönisch, Ulrike
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Hilgers, Valérie
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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https://www.sciencedirect.com/science/article/pii/S0092867423004087?via%3Dihub
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Citation

Alfonso-Gonzalez, C., Legnini, I., Holec, S., Arrigoni, L., Ozbulut, H. C., Mateos, F., et al. (2023). Sites of transcription initiation drive mRNA isoform selection. Cell, 186, 2438-2455. doi:10.1016/j.cell.2023.04.012.

Cite as: https://hdl.handle.net/21.11116/0000-000D-1DBF-D

Abstract

The generation of distinct messenger RNA isoforms through alternative RNA processing modulates the expression and function of genes, often in a cell-type-specific manner. Here, we assess the regulatory relationships between transcription initiation, alternative splicing, and 3' end site selection. Applying long-read sequencing to accurately represent even the longest transcripts from end to end, we quantify mRNA isoforms in Drosophila tissues, including the transcriptionally complex nervous system. We find that in Drosophila heads, as well as in human cerebral organoids, 3' end site choice is globally influenced by the site of transcription initiation (TSS). "Dominant promoters," characterized by specific epigenetic signatures including p300/CBP binding, impose a transcriptional constraint to define splice and polyadenylation variants. In vivo deletion or overexpression of dominant promoters as well as p300/CBP loss disrupted the 3' end expression landscape. Our study demonstrates the crucial impact of TSS choice on the regulation of transcript diversity and tissue identity.