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Regulation of RNA polymerase I and RNA polymerase III transcription by the chromatin remodelling complex B-WICH
Stockholm University, Faculty of Science, The Wenner-Gren Institute. (Ann-Kristin Östlund Farrants)
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ribosomal biogenesis is an important process which determines the rate of cell growth and is involved in cell response to proliferation, differentiation, cellular nutritional state and stress. The chromatin remodelling complex B-WICH composed of WSTF, SNF2h and NM1 is involved in transcription by the RNA pol I and RNA pol III. In this study I investigated the mechanism by which the B-WICH complex modulates the RNA pol I and RNA pol III transcription. I showed that B-WICH binds to the 45S genes, 5S rRNA and 7SL RNA genes, and remodels the chromatin. The remodelling at the 45S genes occurs at the promoter, leading higher accessibility to histone acetyltransferases, such as PCAF and p300. In the RNA pol III transcription, the chromatin outside of the gene is more open, leading to binding of c-Myc, with the subsequent recruitment of histone acetylation resulting in H3-Ac. The importance of the chromatin remodelling around the genes was particularly clear in WSTF knock-down cells, in which the binding of RNA pol III and auxiliary transcription factors at the 5S rRNA and 7SL RNA gene promoters were totally abolished. I concluded that B-WICH functions in a similar manner on both RNA pol I and RNA pol III genes, remodels chromatin locally at the promoter and around the genes, which allows other factors to bind. I also investigated the role of B-WICH in the control of RNA pol I transcription, in the cell cycle and in response to glucose/energy status. My results showed that the B-WICH complex disassembled in prophase, and reassembled at G1. WSTF is hyperphosphorylated in mitosis, and with the dephosphorylation at the end of telophase, the SNF2h and NM1 bind to the WSTF. A reduction of the association of the B-WICH complex is seen in cells treated with inhibitors of different signalling pathways. Furthermore, during glucose deprivation, the level of B-WICH decreases at the RNA pol I promoter. These results demonstrate that the chromatin remodelling complex B-WICH is important in the transcription of RNA pol I and RNA pol III genes, as maintaining the chromatin state in an active configuration. 

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University , 2012. , 47 p.
Keyword [en]
B-WICH, Chromatin remodelling, ribosomal genes, transcription
National Category
Cell Biology
Research subject
Cell Biology
Identifiers
URN: urn:nbn:se:su:diva-75204ISBN: 978-91-7447-513-5 (print)OAI: oai:DiVA.org:su-75204DiVA: diva2:515036
Public defence
2012-05-11, lecture room E306, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Submitted.

Available from: 2012-04-19 Created: 2012-04-11 Last updated: 2017-03-08Bibliographically approved
List of papers
1. The Chromatin Remodelling Complex B-WICH Changes the Chromatin Structure and Recruits Histone Acetyl-Transferases to Active rRNA Genes
Open this publication in new window or tab >>The Chromatin Remodelling Complex B-WICH Changes the Chromatin Structure and Recruits Histone Acetyl-Transferases to Active rRNA Genes
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 4, e19184Article in journal (Refereed) Published
Abstract [en]

The chromatin remodelling complex B-WICH, which comprises the William syndrome transcription factor (WSTF), SNF2h, and nuclear myosin 1 (NM1), is involved in regulating rDNA transcription, and SiRNA silencing of WSTF leads to a reduced level of 45S pre-rRNA. The mechanism behind the action of B-WICH is unclear. Here, we show that the B-WICH complex affects the chromatin structure and that silencing of the WSTF protein results in a compaction of the chromatin structure over a 200 basepair region at the rRNA promoter. WSTF knock down does not show an effect on the binding of the rRNA-specific enhancer and chromatin protein UBF, which contributes to the chromatin structure at active genes. Instead, WSTF knock down results in a reduced level of acetylated H3-Ac, in particular H3K9-Ac, at the promoter and along the gene. The association of the histone acetyl-transferases PCAF, p300 and GCN5 with the promoter is reduced in WSTF knock down cells, whereas the association of the histone acetyl-transferase MOF is retained. A low level of H3-Ac was also found in growing cells, but here histone acetyl-transferases were present at the rDNA promoter. We propose that the B-WICH complex remodels the chromatin structure at actively transcribed rRNA genes, and this allows for the association of specific histone acetyl-transferases.

National Category
Cell Biology
Research subject
Cell Biology
Identifiers
urn:nbn:se:su:diva-68540 (URN)10.1371/journal.pone.0019184 (DOI)000290024700094 ()
Note

7

Available from: 2012-01-04 Created: 2012-01-04 Last updated: 2017-12-08Bibliographically approved
2. The B-WICH chromatin-remodelling complex facilitates the binding of c-Myc and histone acetyl transferases and regulates RNA pol III transcription
Open this publication in new window or tab >>The B-WICH chromatin-remodelling complex facilitates the binding of c-Myc and histone acetyl transferases and regulates RNA pol III transcription
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Transcription of the 5S rRNA genes and 7SL genes by RNA polymerase III is necessary for cell growth and proliferation. The chromatin-remodelling complex B-WICH is associated with these genes, and siRNA-silencing of one component, the WSTF protein, reduces the level of transcription. However, the molecular mechanism is unclear. We show here that the role of B-WICH is to promote the binding of RNA polymerase III and RNA polymerase III factors, TFIIIA, TFIIIB and TFIIIC. WSTF knock down by siRNA resulted in a decreased recruitment of these initiation factors and, consequently, RNA polymerase III, to promoters. In addition, B-WICH induced a local alteration of the chromatin structure around the 5S rRNA and 7SL RNA genes, leading to a reduced acetylation of histone H3, in particular H3K9-Ac. A reduction in the level of WSTF also caused a loss of c-myc binding to the genes. We propose a model in which B-WICH complex is required to maintain an open chromatin structure around these RNA polymerase III genes, a prerequisite for other factors to associate at the gene.

Keyword
B-WICH, chromatin-remodelling, c-Myc, polymerase III, transcription
National Category
Cell Biology
Research subject
Cell Biology
Identifiers
urn:nbn:se:su:diva-75269 (URN)
Available from: 2012-04-12 Created: 2012-04-12 Last updated: 2016-01-29Bibliographically approved
3. Nuclear Myosin 1c Facilitates the Chromatin Modifications Required to Activate rRNA Gene Transcription and Cell Cycle Progression
Open this publication in new window or tab >>Nuclear Myosin 1c Facilitates the Chromatin Modifications Required to Activate rRNA Gene Transcription and Cell Cycle Progression
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2013 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 3, e1003397Article in journal (Refereed) Published
Abstract [en]

Actin and nuclear myosin 1c (NM1) cooperate in RNA polymerase I (pol I) transcription. NM1 is also part of a multiprotein assembly, B-WICH, which is involved in transcription. This assembly contains the chromatin remodeling complex WICH with its subunits WSTF and SNF2h. We report here that NM1 binds SNF2h with enhanced affinity upon impairment of the actin-binding function. ChIP analysis revealed that NM1, SNF2h, and actin gene occupancies are cell cycle-dependent and require intact motor function. At the onset of cell division, when transcription is temporarily blocked, B-WICH is disassembled due to WSTF phosphorylation, to be reassembled on the active gene at exit from mitosis. NM1 gene knockdown and motor function inhibition, or stable expression of NM1 mutants that do not interact with actin or chromatin, overall repressed rRNA synthesis by stalling pol I at the gene promoter, led to chromatin alterations by changing the state of H3K9 acetylation at gene promoter, and delayed cell cycle progression. These results suggest a unique structural role for NM1 in which the interaction with SNF2h stabilizes B-WICH at the gene promoter and facilitates recruitment of the HAT PCAF. This leads to a permissive chromatin structure required for transcription activation.

National Category
Genetics
Research subject
Cell Biology
Identifiers
urn:nbn:se:su:diva-89730 (URN)10.1371/journal.pgen.1003397 (DOI)000316866700068 ()
Funder
Swedish Research CouncilSwedish Cancer Society
Note

AuthorCount:10;

Available from: 2013-05-07 Created: 2013-05-06 Last updated: 2017-12-06Bibliographically approved

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