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Chromatin landscape in transcriptional regulation: A case for ribosomal transcription
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0003-4810-2076
2025 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cell survival, growth, and proliferation are dependent on ribosomal protein synthesis. Ribosome biogenesis is thus a highly regulated process to preserve cell function and survival. It is an energy demanding process that needs to be adapted to nutrient availability and other stimuli. The transcription of 45S rRNA, an essential part of the ribosome machinery, serves as the rate-limiting step.

The work presented in this thesis focuses on the role of a positive regulator of ribosomal transcription – the B-WICH chromatin remodelling complex. We explore the role it plays in rRNA transcription and delve deeper into its mechanisms.

Study I demonstrates that B-WICH is essential to establish and maintain the chromatin accessibility at the rDNA promoter to allow transcription initiation. In the absence of WSTF, a subunit of B-WICH, the ribosomal genes remain inactive and unable to initiate transcription, even upon glucose stimulation. This is because CHD4, as part of NuRD complex, cannot be removed from the promoter thereby rendering it inaccessible.

Study II reveals an interaction between WSTF and noncoding RNA IGS38 at the rDNA promoter. In the absence of IGS38, WSTF is not recruited at the promoter which results in chromatin compaction. Subsequently, RRN3 is also not recruited which directly prevents RNA PolI stabilization and thus transcription is blocked.

Study III investigates the cellular response to ribosomal transcriptional dysregulation in WSTF deficient cells. We reveal that cells respond in a p53 independent manner, and instead trigger an integrative stress response. Moreover, it affects mitochondrial function and increases reliance on mitochondrial respiration. Thus revealing a different response to B-WICH dependent ribosomal stress.

Taken together, these studies establish B-WICH and WSTF at the centre of ribosomal regulation mechanisms. It also demonstrates the important function of chromatin remodelling in essential cellular responses.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2025. , p. 52
Keywords [en]
Ribosomal transcription, chromatin remodelling, WSTF, IGS38, B-WICH, RNA PolI
National Category
Cell and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-237610ISBN: 978-91-8107-074-3 (print)ISBN: 978-91-8107-075-0 (electronic)OAI: oai:DiVA.org:su-237610DiVA, id: diva2:1925548
Public defence
2025-02-21, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius väg 20, Stockholm, 09:00 (English)
Opponent
Supervisors
Available from: 2025-01-29 Created: 2025-01-08 Last updated: 2025-01-22Bibliographically approved
List of papers
1. The chromatin‐remodeling complexes B‐WICH and NuRD regulate ribosomal transcription in response to glucose
Open this publication in new window or tab >>The chromatin‐remodeling complexes B‐WICH and NuRD regulate ribosomal transcription in response to glucose
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2020 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 34, no 8, p. 10818-10834Article in journal (Refereed) Published
Abstract [en]

Regulation of ribosomal transcription is under tight control from environmental stimuli, and this control involves changes in the chromatin structure. The underlying mechanism of how chromatin changes in response to nutrient and energy supply in the cell is still unclear. The chromatin‐remodeling complex B‐WICH is involved in activating the ribosomal transcription, and we show here that knock down of the B‐WICH component WSTF results in cells that do not respond to glucose. The promoter is less accessible, and RNA pol I and its transcription factors SL1/TIF‐1B and RRN3/TIF‐1A, as well as the proto‐oncogene c‐MYC and the activating deacetylase SIRT7 do not bind upon glucose stimulation. In contrast, the repressive chromatin state that forms after glucose deprivation is reversible, and RNA pol I factors are recruited. WSTF knock down results in an accumulation of the ATPase CHD4, a component of the NuRD chromatin remodeling complex, which is responsible for establishing a repressive poised state at the promoter. The TTF‐1, which binds and affect the binding of the chromatin complexes, is important to control the association of activating chromatin component UBF. We suggest that B‐WICH is required to allow for a shift to an active chromatin state upon environmental stimulation, by counteracting the repressive state induced by the NuRD complex.

Keywords
CHD4, chromatin remodeling, c-MYC, ribosomal genes, TTF-1, WSTF
National Category
Cell Biology
Identifiers
urn:nbn:se:su:diva-184041 (URN)10.1096/fj.202000411R (DOI)000546063500001 ()
Available from: 2020-08-12 Created: 2020-08-12 Last updated: 2025-01-08Bibliographically approved
2. IGS38 ncRNA from human rDNA spacer regulates ribosomal transcription and rDNA chromatin organisation
Open this publication in new window or tab >>IGS38 ncRNA from human rDNA spacer regulates ribosomal transcription and rDNA chromatin organisation
(English)Manuscript (preprint) (Other academic)
Keywords
Ribosomal transcription, intergenic spacer, IGS38, B-WICH, chromatin accessibility, chromatin remodelling
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-237608 (URN)
Available from: 2025-01-08 Created: 2025-01-08 Last updated: 2025-01-08
3. Dysregulated ribosomal transcription due to reduced levels of WSTF in the chromatin remodelling complex B-WICH induces the integrative stress response
Open this publication in new window or tab >>Dysregulated ribosomal transcription due to reduced levels of WSTF in the chromatin remodelling complex B-WICH induces the integrative stress response
(English)Manuscript (preprint) (Other academic)
Keywords
B-WICH, ribosomal transcription, chromatin remodelling, integrative stress response, protein translation
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-237609 (URN)
Available from: 2025-01-08 Created: 2025-01-08 Last updated: 2025-01-08

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Tariq, Kanwal

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