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dc.contributor.authorCalvo-Roitberg, Ezequiel
dc.contributor.authorCarroll, Christine L
dc.contributor.authorVenev, Sergey V
dc.contributor.authorKim, GyeungYun
dc.contributor.authorMick, Steven T
dc.contributor.authorDekker, Job
dc.contributor.authorFiszbein, Ana
dc.contributor.authorPai, Athma A
dc.date.accessioned2024-02-22T14:04:07Z
dc.date.available2024-02-22T14:04:07Z
dc.date.issued2024-01-07
dc.identifier.citationCalvo-Roitberg E, Carroll CL, Venev SV, Kim G, Mick ST, Dekker J, Fiszbein A, Pai AA. mRNA initiation and termination are spatially coordinated. bioRxiv [Preprint]. 2024 Jan 7:2024.01.05.574404. doi: 10.1101/2024.01.05.574404. PMID: 38260419; PMCID: PMC10802295.en_US
dc.identifier.doi10.1101/2024.01.05.574404en_US
dc.identifier.pmid38260419
dc.identifier.urihttp://hdl.handle.net/20.500.14038/53083
dc.descriptionThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.en_US
dc.description.abstractThe expression of a precise mRNA transcriptome is crucial for establishing cell identity and function, with dozens of alternative isoforms produced for a single gene sequence. The regulation of mRNA isoform usage occurs by the coordination of co-transcriptional mRNA processing mechanisms across a gene. Decisions involved in mRNA initiation and termination underlie the largest extent of mRNA isoform diversity, but little is known about any relationships between decisions at both ends of mRNA molecules. Here, we systematically profile the joint usage of mRNA transcription start sites (TSSs) and polyadenylation sites (PASs) across tissues and species. Using both short and long read RNA-seq data, we observe that mRNAs preferentially using upstream TSSs also tend to use upstream PASs, and congruently, the usage of downstream sites is similarly paired. This observation suggests that mRNA 5' end choice may directly influence mRNA 3' ends. Our results suggest a novel "Positional Initiation-Termination Axis" (PITA), in which the usage of alternative terminal sites are coupled based on the order in which they appear in the genome. PITA isoforms are more likely to encode alternative protein domains and use conserved sites. PITA is strongly associated with the length of genomic features, such that PITA is enriched in longer genes with more area devoted to regions that regulate alternative 5' or 3' ends. Strikingly, we found that PITA genes are more likely than non-PITA genes to have multiple, overlapping chromatin structural domains related to pairing of ordinally coupled start and end sites. In turn, PITA coupling is also associated with fast RNA Polymerase II (RNAPII) trafficking across these long gene regions. Our findings indicate that a combination of spatial and kinetic mechanisms couple transcription initiation and mRNA 3' end decisions based on ordinal position to define the expression mRNA isoforms.en_US
dc.language.isoenen_US
dc.relation.ispartofbioRxiven_US
dc.relation.urlhttps://doi.org/10.1101/2024.01.05.574404en_US
dc.rightsThe copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.en_US
dc.rightsAttribution-NonCommercial 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/*
dc.subjectGenomicsen_US
dc.subjectmRNAen_US
dc.subjectPositional Initiation-Termination Axisen_US
dc.titlemRNA initiation and termination are spatially coordinated [preprint]en_US
dc.typePreprinten_US
dc.source.journaltitlebioRxiv : the preprint server for biology
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.identifier.journalbioRxiv : the preprint server for biology
refterms.dateFOA2024-02-22T14:04:08Z
dc.contributor.departmentMorningside Graduate School of Biomedical Sciencesen_US
dc.contributor.departmentRNA Therapeutics Instituteen_US
dc.contributor.departmentSystems Biologyen_US
dc.contributor.studentEzequiel Calvo-Roitberg


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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
Except where otherwise noted, this item's license is described as The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.