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Sites of transcription initiation drive mRNA isoform selection

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Item Type:Article
Title:Sites of transcription initiation drive mRNA isoform selection
Creators Name:Alfonso-Gonzalez, C. and Legnini, I. and Holec, S. and Arrigoni, L. and Ozbulut, H.C. and Mateos, F. and Koppstein, D. and Rybak-Wolf, A. and Bönisch, U. and Rajewsky, N. and Hilgers, V.
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.
Keywords:Transcription, mRNA Isoform, 5'-3' Coupling, Transcription Start Site, Alternative Polyadenylation, Long-Read Sequencing, Human Brain Organoids, Nervous System, p300/CBP
Publisher:Cell Press
Page Range:2438-2455
Date:25 May 2023
Official Publication:https://doi.org/10.1016/j.cell.2023.04.012
PubMed:View item in PubMed

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