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Gene regulation by chromatin remodelling complexes: SWI/SNF complex in mRNA processing and B-WICH complex in ribosomal gene expression
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this project is to investigate the roles of chromatin remodelling complexes in gene regulation. It is focused on two groups of chromatin complexes: the mammalian BRG1 and BRM SWI/SNF complexes and the ISWI-containing B-WICH complex.

Study 1 investigates the role of SWI/SNF complexes in alternative splicing. We show that the presence of the ATPase core subunits Brg1 and Brm influence the alternative splicing outcome of a subset of genes. We show that Brg1 and Brm interact with several splicing related factors in the nascent RNA, and that the recruitment of some of these factors to their target sites is regulated by the presence of Brg1 and Brm. We propose that SWI/SNF ATPases can modulate the interactions of RNA binding factors to the nascent RNA and in that way alter alternative splicing outcome.

Study 2 focuses on SWI/SNF complexes and their influence on cleavage and polyadenylation of mRNA. We show that Brg1 and Brm interact with subunits of the cleavage and polyadenylation complexes in the nascent mRNA. SWI/SNF complexes facilitate the recruitment of the cleavage and polyadenylation complex to the polyadenylation site in a subset of genes, and this results in a more efficient cleavage and polyadenylation.

Study 3 shows that B-WICH is required for ribosome gene transcriptional activation upon glucose stimulation. WSTF and SNF2h, two of the B-WICH subunits, are needed to establish an active chromatin state in the RNA pol I gene promoter when the glucose concentration is raised after a period of deprivation. We propose that it counteracts the silent, poised chromatin state imposed by the silencing chromatin remodelling complex NuRD to allow for the RNA pol I machinery to bind to the promoter.

These studies show that the influence of chromatin remodelling complexes upon gene expression is important for remodelling nucleosomes at the promoter, for alternative splicing, cleavage and polyadenylation and transcriptional initiation. These complexes work together with other chromatin remodelling factors, interact with other complexes and regulate their activity by affecting their recruitment dynamics.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2018.
Keywords [en]
Chromatin remodelling, SWI/SNF, Brg1, Brm, alternative splicing, cleavage and polyadenylation, B-WICH, WSTF, ribosomal genes
National Category
Cell and Molecular Biology
Research subject
Cell Biology
Identifiers
URN: urn:nbn:se:su:diva-161380ISBN: 978-91-7797-504-5 (print)ISBN: 978-91-7797-505-2 (electronic)OAI: oai:DiVA.org:su-161380DiVA, id: diva2:1258091
Public defence
2018-12-07, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius väg 20, Stockholm, 09:15 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Manuscript. Paper 3: Manuscript.

Available from: 2018-11-14 Created: 2018-10-23 Last updated: 2018-11-07Bibliographically approved
List of papers
1. SWI/SNF subunits Brg1 and Brm regulate alternative splicing by interacting with RNA binding proteins in the nascent RNA.
Open this publication in new window or tab >>SWI/SNF subunits Brg1 and Brm regulate alternative splicing by interacting with RNA binding proteins in the nascent RNA.
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Research subject
Cell Biology
Identifiers
urn:nbn:se:su:diva-161375 (URN)
Available from: 2018-10-23 Created: 2018-10-23 Last updated: 2018-10-24Bibliographically approved
2. SWI/SNF interacts with cleavage and polyadenylation factors and facilitates pre-mRNA 3' end processing
Open this publication in new window or tab >>SWI/SNF interacts with cleavage and polyadenylation factors and facilitates pre-mRNA 3' end processing
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2018 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 16, p. 8557-8573Article in journal (Refereed) Published
Abstract [en]

SWI/SNF complexes associate with genes and regulate transcription by altering the chromatin at the promoter. It has recently been shown that these complexes play a role in pre-mRNA processing by associating at alternative splice sites. Here, we show that SWI/SNF complexes are involved also in pre-mRNA 3′ end maturation by facilitating 3′ end cleavage of specific pre-mRNAs. Comparative proteomics show that SWI/SNF ATPases interact physically with subunits of the cleavage and polyadenylation complexes in fly and human cells. In Drosophila melanogaster, the SWI/SNF ATPase Brahma (dBRM) interacts with the CPSF6 subunit of cleavage factor I. We have investigated the function of dBRM in 3′ end formation in S2 cells by RNA interference, single-gene analysis and RNA sequencing. Our data show that dBRM facilitates pre-mRNA cleavage in two different ways: by promoting the association of CPSF6 to the cleavage region and by stabilizing positioned nucleosomes downstream of the cleavage site. These findings show that SWI/SNF complexes play a role also in the cleavage of specific pre-mRNAs in animal cells.

National Category
Cell and Molecular Biology
Research subject
Cell Biology
Identifiers
urn:nbn:se:su:diva-161378 (URN)10.1093/nar/gky438 (DOI)
Available from: 2018-10-23 Created: 2018-10-23 Last updated: 2018-10-24Bibliographically approved
3. The chromatin remodelling complex B-WICH is required for transcriptional activation of the ribosomal transcription by glucose stimulation.
Open this publication in new window or tab >>The chromatin remodelling complex B-WICH is required for transcriptional activation of the ribosomal transcription by glucose stimulation.
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(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Research subject
Cell Biology
Identifiers
urn:nbn:se:su:diva-161376 (URN)
Available from: 2018-10-23 Created: 2018-10-23 Last updated: 2018-10-24Bibliographically approved

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