![]() Thus, resolving full transcript structures and accurate quantification of the abundance of alternative transcripts are important steps towards the detection and understanding of these mechanisms. Whether these processes are co-transcriptionally linked is currently largely unknown, as are the mechanisms that couple transcription with 5′ end capping, splicing, and 3′ end formation (reviewed in ). Tight regulation and coordination of these processes ensures the production of a (limited) set of cell-, tissue-, and condition-specific transcript variants to meet variable cellular protein requirements. The multitude of transcripts arising from these events offers an enormous diversity of protein isoforms that can be produced from a single gene locus. In higher eukaryotes, variations in each of these steps, including alternative transcription initiation, differential splicing of exons, and alternative polyadenylation site usage, change the content of the mature transcript. The formation of a mature messenger RNA (mRNA) is a multi-step process. Our findings demonstrate that our understanding of transcriptome complexity is far from complete and provides a basis to reveal largely unresolved mechanisms that coordinate transcription initiation and mRNA processing. ![]() By recognizing sample-specific amino-acid changes and novel splicing patterns, full-length mRNA sequencing improves proteogenomics analysis of MCF-7 cells. The mapping database rescues 358 previously unassigned peptides and improves the assignment of others. We predict thousands of novel open reading frames from full-length mRNA sequences and obtained evidence for their translation by shotgun proteomics. The analysis of three human primary tissues (brain, heart and liver) reveals similar patterns of interdependency between transcription initiation and mRNA processing events. In MCF-7 breast cancer cells, we find 2700 genes with interdependent alternative transcription initiation, splicing and polyadenylation events, both in proximal and distant parts of mRNA molecules, including examples of coupling between transcription start sites and polyadenylation sites. Here, we studied the interdependence of transcription initiation, splicing and polyadenylation events on single mRNA molecules by full-length mRNA sequencing. The multifaceted control of gene expression requires tight coordination of regulatory mechanisms at transcriptional and post-transcriptional level.
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