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Dissecting gene expression regulation in mouse embryonic stems
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).
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: urn:nbn:se:umu:diva-206718ISBN: 978-91-8070-073-3 (print)ISBN: 978-91-8070-074-0 (electronic)OAI: oai:DiVA.org:umu-206718DiVA, id: diva2:1750785
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
List of papers
1. The catalytic-independent function of LSD1 modulates the epigenetic landscape of mouse embryonic stem cells
Open this publication in new window or tab >>The catalytic-independent function of LSD1 modulates the epigenetic landscape of mouse embryonic stem cells
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(English)Manuscript (preprint) (Other academic)
Keywords
LSD1, DNA methylation, DNMT1, UHRF1 and USP7
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-206715 (URN)
Available from: 2023-04-14 Created: 2023-04-14 Last updated: 2023-04-14
2. LSD1 interacts with CHD7 to regulate the chromatin landscape in mouse embryonic stem cells
Open this publication in new window or tab >>LSD1 interacts with CHD7 to regulate the chromatin landscape in mouse embryonic stem cells
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

 

 

 

National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-206717 (URN)
Available from: 2023-04-14 Created: 2023-04-14 Last updated: 2023-04-14
3. ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export
Open this publication in new window or tab >>ZFP207 sustains pluripotency by coordinating OCT4 stability, alternative splicing and RNA export
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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
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-191672 (URN)10.15252/embr.202153191 (DOI)000743102200001 ()35037361 (PubMedID)2-s2.0-85122763926 (Scopus ID)
Available from: 2022-01-21 Created: 2022-01-21 Last updated: 2024-04-08Bibliographically approved

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Malla, Sandhya

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