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The SWI/SNF subunit BRG1 affects alternative splicing by changing RNA binding factor interactions with nascent RNA
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0002-6852-4834
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Science for Life Laboratory (SciLifeLab).ORCID iD: 0000-0003-1673-5389
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0003-0556-2531
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Number of Authors: 82022 (English)In: Molecular Genetics and Genomics, ISSN 1617-4615, E-ISSN 1617-4623, Vol. 297, no 2, p. 463-484Article in journal (Refereed) Published
Abstract [en]

BRG1 and BRM are ATPase core subunits of the human SWI/SNF chromatin remodelling complexes mainly associated with transcriptional initiation. They also have a role in alternative splicing, which has been shown for BRM-containing SWI/SNF complexes at a few genes. Here, we have identified a subset of genes which harbour alternative exons that are affected by SWI/SNF ATPases by expressing the ATPases BRG1 and BRM in C33A cells, a BRG1- and BRM-deficient cell line, and analysed the effect on splicing by RNA sequencing. BRG1- and BRM-affected sub-sets of genes favouring both exon inclusion and exon skipping, with only a minor overlap between the ATPase. Some of the changes in alternative splicing induced by BRG1 and BRM expression did not require the ATPase activity. The BRG1-ATPase independent included exons displayed an exon signature of a high GC content. By investigating three genes with exons affected by the BRG-ATPase-deficient variant, we show that these exons accumulated phosphorylated RNA pol II CTD, both serine 2 and serine 5 phosphorylation, without an enrichment of the RNA polymerase II. The ATPases were recruited to the alternative exons, together with both core and signature subunits of SWI/SNF complexes, and promoted the binding of RNA binding factors to chromatin and RNA at the alternative exons. The interaction with the nascent RNP, however, did not reflect the association to chromatin. The hnRNPL, hnRNPU and SAM68 proteins associated with chromatin in cells expressing BRG1 and BRM wild type, but the binding of hnRNPU to the nascent RNP was excluded. This suggests that SWI/SNF can regulate alternative splicing by interacting with splicing-RNA binding factor and influence their binding to the nascent pre-mRNA particle.

Place, publisher, year, edition, pages
2022. Vol. 297, no 2, p. 463-484
Keywords [en]
mRNA alternative splicing, Exon GC content, Chromatin remodelling, SWI/SNF, BRGG1, hnRNPL, hnRNPU, SAM68
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-202889DOI: 10.1007/s00438-022-01863-9ISI: 000758072300001PubMedID: 35187582Scopus ID: 2-s2.0-85124836307OAI: oai:DiVA.org:su-202889DiVA, id: diva2:1645563
Available from: 2022-03-18 Created: 2022-03-18 Last updated: 2022-03-30Bibliographically approved

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Gañez-Zapater, AntoniMackowiak, Sebastian D.Guo, YuanTarbier, MarcelJordán-Pla, AntonioFriedländer, Marc R.Visa, NeusÖstlund Farrants, Ann-Kristin

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Gañez-Zapater, AntoniMackowiak, Sebastian D.Guo, YuanTarbier, MarcelJordán-Pla, AntonioFriedländer, Marc R.Visa, NeusÖstlund Farrants, Ann-Kristin
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Department of Molecular Biosciences, The Wenner-Gren InstituteScience for Life Laboratory (SciLifeLab)
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