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The Chromatin Remodelling Complex B-WICH Changes the Chromatin Structure and Recruits Histone Acetyl-Transferases to Active rRNA Genes
Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
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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.

Place, publisher, year, edition, pages
2011. Vol. 6, no 4, e19184
National Category
Cell Biology
Research subject
Cell Biology
Identifiers
URN: urn:nbn:se:su:diva-68540DOI: 10.1371/journal.pone.0019184ISI: 000290024700094OAI: oai:DiVA.org:su-68540DiVA: diva2:472785
Note

7

Available from: 2012-01-04 Created: 2012-01-04 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Regulation of RNA polymerase I and RNA polymerase III transcription by the chromatin remodelling complex B-WICH
Open this publication in new window or tab >>Regulation of RNA polymerase I and RNA polymerase III transcription by the chromatin remodelling complex B-WICH
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
B-WICH, Chromatin remodelling, ribosomal genes, transcription
National Category
Cell Biology
Research subject
Cell Biology
Identifiers
urn:nbn:se:su:diva-75204 (URN)978-91-7447-513-5 (ISBN)
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
2. Non-protein-coding RNA: Transcription and regulation of ribosomal RNA
Open this publication in new window or tab >>Non-protein-coding RNA: Transcription and regulation of ribosomal RNA
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cell growth and proliferation are processes in the cell that must be tightly regulated. Transcription of ribosomal RNA and ribosomal biogenesis are directly linked to cell growth and proliferation, since the ribosomal RNA encodes for the majority of transcription in a cell and ribosomal biogenesis influences directly the number of proteins that are synthesized.

In the work presented in this thesis, we have investigated the ribosomal RNA genes, namely the ribosomal DNA genes and the 5S rRNA genes, and their transcriptional regulation. One protein complex that is involved in RNA polymerase I and III transcription is the chromatin remodelling complex B‑WICH (WSTF, SNF2h, NM1). RNA polymerase I transcribes the rDNA gene, while RNA polymerase III transcribes the 5S rRNA gene, among others. In Study I we determined the mechanism by which B‑WICH is involved in regulating RNA polymerase I transcription. B‑WICH is associated with the rDNA gene and was able to create a more open chromatin structure, thereby facilitating the binding of HATs and the subsequent histone acetylation. This resulted in a more active transcription of the ribosomal DNA gene. In Study II we wanted to specify the role of NM1 in RNA polymerase I transcription. We found that NM1 is not capable of remodelling chromatin in the same way as B‑WICH, but we demonstrated also that NM1 is needed for active RNA polymerase I transcription and is able to attract the HAT PCAF. In Study III we investigated the intergenic part of the ribosomal DNA gene. We detected non-coding RNAs transcribed from the intergenic region that are transcribed by different RNA polymerases and that are regulated differently in different stress situations. Furthermore, these ncRNAs are distributed at different locations in the cell, suggesting that they have different functions. In Study IV we showed the involvement of B‑WICH in RNA Pol III transcription and, as we previously had shown in Study I, that B‑WICH is able to create a more open chromatin structure, in this case by acting as a licensing factor for c-Myc and the Myc/Max/Mxd network.

Taken together, we have revealed the mechanism by which the B‑WICH complex is able to regulate RNA Pol I and Pol III transcription and we have determined the role of NM1 in the B‑WICH complex. We conclude that B‑WICH is an important factor in the regulation of cell growth and proliferation. Furthermore, we found that the intergenic spacer of the rDNA gene is actively transcribed, producing ncRNAs. Different cellular locations suggest that the ncRNAs have different functions.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2014. 58 p.
Keyword
ribosomal RNA, non-coding RNA, ribosomal genes, rDNA gene, B-WICH, chromatin remodelling, histone modification
National Category
Cell Biology
Research subject
Cell Biology
Identifiers
urn:nbn:se:su:diva-102718 (URN)978-91-7447-906-5 (ISBN)
Public defence
2014-05-23, Lecture hall E306, Arrheniuslaboratorierna, Svante Arrhenius Väg 20 C, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defence the following papers were unpublished and had a status as follows: Paper 2: Manuscript; Paper 3: Manuscript

Available from: 2014-04-29 Created: 2014-04-16 Last updated: 2014-04-29Bibliographically approved
3. Chromatin remodelling of ribosomal genes - be bewitched by B-WICH
Open this publication in new window or tab >>Chromatin remodelling of ribosomal genes - be bewitched by B-WICH
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transcription of the ribosomal genes accounts for the majority of transcription in the cell due to the constant high demand for ribosomes. The number of proteins synthesized correlates with an effective ribosomal biogenesis, which is regulated by cell growth and proliferation. In the work presented in this thesis, we have investigated the ribosomal RNA genes 45S and 5S rRNA, which are transcribed by RNA Pol I and RNA Pol III, respectively.

The focus of this work is the chromatin remodelling complex B-WICH, which is composed of WSTF, the ATPase SNF2h and NM1. We have studied in particular its role in ribosomal gene transcription. We showed in Study I that B-WICH is required to set the stage at rRNA gene promoters by remodelling the chromatin into an open, transcriptionally active configuration. This results in the binding of histone acetyl transferases to the genes and subsequent histone acetylation, which is needed for ribosomal gene activation. Study II investigated the role of B-WICH in transcription mediated by RNA polymerase III. We showed that B-WICH is essential to create an accessible chromatin atmosphere at 5S rRNA genes, which is compatible with the results obtained in Study 1. In this case, however, B-WICH operates as a licensing factor for c-Myc and the Myc/Max/Mxd network. Study III confirmed the importance and the function of the B-WICH complex as an activator of ribosomal genes. We demonstrated that B-WICH is important for the remodelling of the rDNA chromatin into an active, competent state in response to extracellular stimuli, and that the association of the B-WICH complex to the rRNA gene promoter is regulated by proliferative and metabolic changes in cells.

The work presented in this thesis has confirmed that the B-WICH complex is an important regulator and activator of Pol I and Pol III transcription. We conclude that B-WICH is essential for remodelling the rDNA chromatin into a transcriptionally active state, as required for efficient ribosomal gene transcription.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2015
Keyword
chromatin remodelling, ribosomal genes, rDNA, transcription, RNA polymerase I transcription, RNA polymerase III transcription
National Category
Cell Biology
Research subject
Cell Biology
Identifiers
urn:nbn:se:su:diva-115530 (URN)978-91-7649-024-2 (ISBN)
Public defence
2015-05-05, room E306, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 10:00 (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: Manuscript.

 

Available from: 2015-04-13 Created: 2015-03-25 Last updated: 2017-03-08Bibliographically approved

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