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Nuclear Myosin 1c Facilitates the Chromatin Modifications Required to Activate rRNA Gene Transcription and Cell Cycle Progression
Stockholm University, Faculty of Science, The Wenner-Gren Institute, Cell Biology.
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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.

Place, publisher, year, edition, pages
2013. Vol. 9, no 3, e1003397
National Category
Genetics
Research subject
Cell Biology
Identifiers
URN: urn:nbn:se:su:diva-89730DOI: 10.1371/journal.pgen.1003397ISI: 000316866700068OAI: oai:DiVA.org:su-89730DiVA: diva2:620081
Funder
Swedish Research CouncilSwedish Cancer Society
Note

AuthorCount:10;

Available from: 2013-05-07 Created: 2013-05-06 Last updated: 2017-12-06Bibliographically approved
In thesis
1. 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
2. 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

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