Sites of transcription initiation drive mRNA isoform selection.

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

Cell 2023 May 25

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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. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Carlos Alfonso-Gonzalez, Ivano Legnini, Sarah Holec, Laura Arrigoni, Hasan Can Ozbulut, Fernando Mateos, David Koppstein, Agnieszka Rybak-Wolf, Ulrike Bönisch, Nikolaus Rajewsky, Valérie Hilgers. Sites of transcription initiation drive mRNA isoform selection. Cell. 2023 May 25;186(11):2438-2455.e22