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ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export
Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).ORCID iD: 0000-0002-5389-244X
Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
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2022 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 23, no 3, article id e53191Article in journal (Refereed) Published
Abstract [en]

The pluripotent state is not solely governed by the action of the core transcription factors OCT4, SOX2, and NANOG, but also by a series of co-transcriptional and post-transcriptional events, including alternative splicing (AS) and the interaction of RNA-binding proteins (RBPs) with defined subpopulations of RNAs. Zinc Finger Protein 207 (ZFP207) is an essential transcription factor for mammalian embryonic development. Here, we employ multiple functional analyses to characterize its role in mouse embryonic stem cells (ESCs). We find that ZFP207 plays a pivotal role in ESC maintenance, and silencing of Zfp207 leads to severe neuroectodermal differentiation defects. In striking contrast to human ESCs, mouse ZFP207 does not transcriptionally regulate neuronal and stem cell-related genes but exerts its effects by controlling AS networks and by acting as an RBP. Our study expands the role of ZFP207 in maintaining ESC identity, and underscores the functional versatility of ZFP207 in regulating neural fate commitment.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022. Vol. 23, no 3, article id e53191
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-191672DOI: 10.15252/embr.202153191ISI: 000743102200001PubMedID: 35037361Scopus ID: 2-s2.0-85122763926OAI: oai:DiVA.org:umu-191672DiVA, id: diva2:1630786
Available from: 2022-01-21 Created: 2022-01-21 Last updated: 2024-04-08Bibliographically approved
In thesis
1. Dissecting gene expression regulation in mouse embryonic stems
Open this publication in new window or tab >>Dissecting gene expression regulation in mouse embryonic stems
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Every cell within an organism is derived from a single fertilized egg that undergoes cellular differentiation and development to generate mature specialized cells. Mouse embryonic stem cells (ESCs) derived from the inner cell mass (ICM) of the pre-implantation blastocyst have proven to be a model to study gene expression during differentiation and development. In this thesis, we integrate different layers of gene expression programs, from epigenetics to post-translational regulation, to unravel the intricate network of pluripotency and differentiation in ESCs.

We show that Lysine-specific histone demethylase 1 (LSD1), an epigenetic regulator that removes mono- and di-methyl groups from lysine 4 of histone H3 (H3K4), is not essential for ESC self-renewal. However, the enzymatic activity of LSD1 is indispensable for differentiation. We observe a gain of H3K4me1 in the regulatory regions of pluripotency genes in Lsd1 knockout (KO) ESCs that do not alter gene expression programs related to the ESC state. Additionally, we uncover that independently of its catalytic activity, LSD1 stabilizes the DNA maintenance methylation machinery, such as DNMT1 and UHRF1 proteins, through interaction with ubiquitin-specific peptidase 7 (USP7), which ultimately maintains the DNA methylation equilibrium in the ESC state.

Furthermore, we identify chromodomain-helicase-DNA binding protein 7 (CHD7) as a novel interacting partner of LSD1 in ESCs. CHD7 is an ATP-dependent chromatin remodeler that regulates cell type-specific gene expression, specifically during neurogenesis. Herein, we show that Chd7/Lsd1 double KO ESCs showed a severe defect in differentiation, whereas Chd7 KO ESCs differentiated with mild dysregulation of ectodermal markers. This data suggests that there is a crosstalk between epigenetic regulators which mediate a distinct set of gene expression programs during lineage-specific commitment.

Besides the core pluripotency factors OCT4, SOX2, and NANOG, a cascade of co-transcriptional events such as alternative splicing (AS) and regulation by RNA binding proteins (RBP) also play a critical role in self-renewal and cell-fate decisions. Indeed, we identify Zinc Finger Protein 207 (ZFP207) as a novel RBP, essential to maintain ESC identity in vitro. In addition to impaired neuroectodermal differentiation, we also find abnormal AS events that lead to a differentiated cell-like pattern upon depletion of ZFP207 in ESCs.Altogether, the work of this thesis illustrates the complexity of gene expression regulation that modulates pluripotency and differentiation.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2023. p. 87
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2248
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-206718 (URN)978-91-8070-073-3 (ISBN)978-91-8070-074-0 (ISBN)
Public defence
2023-05-12, Major Groove, Department of Molecular Biology, University hospital area, building 6L, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2023-04-21 Created: 2023-04-14 Last updated: 2024-05-12Bibliographically approved
2. RNA-mediated gene expression regulation
Open this publication in new window or tab >>RNA-mediated gene expression regulation
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
RNA-medierad genuttrycksreglering
Abstract [en]

The regulation of gene expression is a key mechanism that underlies all biological processes, from embryonic development to the onset and progression of various diseases, including cancer. A growing body of evidence places RNA molecules at the center of critical regulatory steps in gene expression. They serve not only as intermediate molecules between DNA and proteins but also act as regulators of processes such as alternative splicing (AS) and translation, among others. This thesis focuses on the role of RNA in gene expression regulation. Specifically, it addresses how intrinsic properties of RNA, RNA chemical modifications, and RNA binding proteins (RBPs) can control gene expression regulatory processes.

The first part tackles specific aspects of AS in neurodifferentiation. Paper I shows how RBPs affect AS in mouse embryonic stem cells (ESCs). Within this work, we identified ZFP207, a known transcription factor (TF), as an RBP with a crucial role in modulating the AS of key transcripts for neurodifferentiation. Depletion of ZFP207 in mouse ESCs led to abnormal AS patterns and a differentiated cell phenotype.

The second part (Papers II-IV) focuses on the role of RNA modifications in disease. In Paper II, the publicly available literature linking deregulations of RNA modifications and their regulatory proteins with different diseases was curated. The obtained information was integrated into the 2021 update of the MODOMICS database, the most extensive RNA modifications database to date. Papers III and IV exemplify how two different RNA marks contribute to breast cancer. Paper III shows how METTL3, the enzyme responsible for N6-methyladenosine (m6A) deposition on messenger RNA (mRNA), affects tumorigenesis by modulating AS. METTL3-mediated AS regulation can be done either by depositing m6A at the intron-exon junctions of specific transcripts or on transcripts encoding for splicing and transcription factors, such as MYC. Changes in RNA modifications of ribosomal RNA (rRNA) affect stability, folding, and interactions with other molecules, leading to perturbed translation efficiency (TE). In Paper IV, we focused on the role of 2'-O-methylation, the most abundant rRNA modification, and its catalytic enzyme, fibrillarin (FBL), in triple-negative breast cancer (TNBC). We discovered that certain proto-oncogenes associated with breast cancer displayed a reduction in TE upon FBL depletion. Additionally, we identified 7 2'-O-methylation sites that might mediate TE regulation in a TNBC cellular model. Moreover, our study uncovered alterations in the ribosomal protein composition within the ribosomes of FBL-depleted cells. Our results support the pivotal role of 2'-O-methylation in controlling the translational capabilities of ribosomes in TNBC cells.

Overall, this work encompasses multiple aspects of gene expression regulation and describes how RNA modifications and RBPs modulate the fate of specific transcripts by controlling AS or translation.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. p. 109
Series
Doctoral thesis / Umeå University, Department of Molecular Biology ; 2301
Keywords
RNA modifications, fibrillarin, 2'-O-methylation, translation, alternative splicing, METTL3, m6A, ZFP207, breast cancer, mouse ESCs
National Category
Basic Medicine
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-223013 (URN)978-91-8070-372-7 (ISBN)978-91-8070-371-0 (ISBN)
Public defence
2024-05-03, Major Groove, Department of Molecular Biology, University hospital area, building 6L, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2024-04-12 Created: 2024-04-08 Last updated: 2024-04-12Bibliographically approved

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Malla, SandhyaBhattarai, Devi PrasadGroza, PaulaMelguizo-Sanchis, DarioMartinez Gamero, CarlosAguilo, Francesca

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