Gain of 1q confers an MDM4-driven growth advantage to undifferentiated and differentiating hESC while altering their differentiation capacity

Nusa Krivec; Edouard Couvreu De Deckersberg; Yingnan Lei; Diana Al Delbany; Marius Regin; Stefaan Verhulst; Leo A van Grunsven; Karen Sermon; Claudia Spits

doi:https://doi.org/10.1038/s41419-024-07236-x

Gain of 1q confers an MDM4-driven growth advantage to undifferentiated and differentiating hESC while altering their differentiation capacity

Nusa Krivec, Edouard Couvreu De Deckersberg, Yingnan Lei, Diana Al Delbany, Marius Regin, Stefaan Verhulst, Leo A van Grunsven, Karen Sermon, Claudia Spits

Research output: Contribution to journal › Article › peer-review

Abstract

Gain of 1q is a highly recurrent chromosomal abnormality in human pluripotent stem cells. In this work, we show that gains of 1q impact the differentiation capacity to derivates of the three germ layers, leading to mis-specification to cranial placode and non-neural ectoderm during neuroectoderm differentiation. Also, we found a weaker expression of lineage-specific markers in hepatoblasts and cardiac progenitors. Competition assays show that the cells retain their selective advantage during differentiation, which is mediated by a higher expression of MDM4, a gene located in the common region of gain. MDM4 drives the winner phenotype of the mutant cells in both the undifferentiated and differentiating state by reducing the cells’ sensitivity to DNA damage through decreased p53-mediated apoptosis. Finally, we found that cell density in culture plays a key role in promoting the competitive advantage of the cells by increasing DNA damage.

Original language	English
Article number	852
Number of pages	14
Journal	Cell Death and Disease
Volume	15
DOIs	https://doi.org/10.1038/s41419-024-07236-x
Publication status	Published - 21 Nov 2024

Bibliographical note

Funding Information:
The authors wish to thank Kristoffer Riecken of the University of Hamburg for kindly sharing the lentiviral constructs for the overexpression of the fluorescent proteins mCherry and Venus. Thanks also go to Yannick De Vlaeminck for assistance with the production of lentivirus and for kindly sharing the modified GFP plasmid. YL is a predoctoral fellow supported by the China Scholarship Council (CSC), and NK, MR and ECDD are predoctoral fellows supported by the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO, grant numbers 1169023N, 1133622N, 1S73521N). This research was supported by the Methusalem Grant to KS and CS (Vrije Universitet Brussel).

Publisher Copyright:
© The Author(s) 2024.

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https://doi.org/10.1038/s41419-024-07236-x

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Krivec, Nusa ; Couvreu De Deckersberg, Edouard ; Lei, Yingnan ; Al Delbany, Diana ; Regin, Marius ; Verhulst, Stefaan ; van Grunsven, Leo A ; Sermon, Karen ; Spits, Claudia. / Gain of 1q confers an MDM4-driven growth advantage to undifferentiated and differentiating hESC while altering their differentiation capacity. In: Cell Death and Disease. 2024 ; Vol. 15.

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title = "Gain of 1q confers an MDM4-driven growth advantage to undifferentiated and differentiating hESC while altering their differentiation capacity",

abstract = "Gain of 1q is a highly recurrent chromosomal abnormality in human pluripotent stem cells. In this work, we show that gains of 1q impact the differentiation capacity to derivates of the three germ layers, leading to mis-specification to cranial placode and non-neural ectoderm during neuroectoderm differentiation. Also, we found a weaker expression of lineage-specific markers in hepatoblasts and cardiac progenitors. Competition assays show that the cells retain their selective advantage during differentiation, which is mediated by a higher expression of MDM4, a gene located in the common region of gain. MDM4 drives the winner phenotype of the mutant cells in both the undifferentiated and differentiating state by reducing the cells{\textquoteright} sensitivity to DNA damage through decreased p53-mediated apoptosis. Finally, we found that cell density in culture plays a key role in promoting the competitive advantage of the cells by increasing DNA damage.",

author = "Nusa Krivec and {Couvreu De Deckersberg}, Edouard and Yingnan Lei and {Al Delbany}, Diana and Marius Regin and Stefaan Verhulst and {van Grunsven}, {Leo A} and Karen Sermon and Claudia Spits",

note = "Funding Information: The authors wish to thank Kristoffer Riecken of the University of Hamburg for kindly sharing the lentiviral constructs for the overexpression of the fluorescent proteins mCherry and Venus. Thanks also go to Yannick De Vlaeminck for assistance with the production of lentivirus and for kindly sharing the modified GFP plasmid. YL is a predoctoral fellow supported by the China Scholarship Council (CSC), and NK, MR and ECDD are predoctoral fellows supported by the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO, grant numbers 1169023N, 1133622N, 1S73521N). This research was supported by the Methusalem Grant to KS and CS (Vrije Universitet Brussel). Publisher Copyright: {\textcopyright} The Author(s) 2024.",

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doi = "https://doi.org/10.1038/s41419-024-07236-x",

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Gain of 1q confers an MDM4-driven growth advantage to undifferentiated and differentiating hESC while altering their differentiation capacity. / Krivec, Nusa ; Couvreu De Deckersberg, Edouard ; Lei, Yingnan ; Al Delbany, Diana ; Regin, Marius ; Verhulst, Stefaan ; van Grunsven, Leo A ; Sermon, Karen ; Spits, Claudia.

In: Cell Death and Disease, Vol. 15, 852, 21.11.2024.

Research output: Contribution to journal › Article › peer-review

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AU - Krivec, Nusa

AU - Couvreu De Deckersberg, Edouard

AU - Lei, Yingnan

AU - Al Delbany, Diana

AU - Regin, Marius

AU - Verhulst, Stefaan

AU - van Grunsven, Leo A

AU - Sermon, Karen

AU - Spits, Claudia

N1 - Funding Information: The authors wish to thank Kristoffer Riecken of the University of Hamburg for kindly sharing the lentiviral constructs for the overexpression of the fluorescent proteins mCherry and Venus. Thanks also go to Yannick De Vlaeminck for assistance with the production of lentivirus and for kindly sharing the modified GFP plasmid. YL is a predoctoral fellow supported by the China Scholarship Council (CSC), and NK, MR and ECDD are predoctoral fellows supported by the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO, grant numbers 1169023N, 1133622N, 1S73521N). This research was supported by the Methusalem Grant to KS and CS (Vrije Universitet Brussel). Publisher Copyright: © The Author(s) 2024.

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N2 - Gain of 1q is a highly recurrent chromosomal abnormality in human pluripotent stem cells. In this work, we show that gains of 1q impact the differentiation capacity to derivates of the three germ layers, leading to mis-specification to cranial placode and non-neural ectoderm during neuroectoderm differentiation. Also, we found a weaker expression of lineage-specific markers in hepatoblasts and cardiac progenitors. Competition assays show that the cells retain their selective advantage during differentiation, which is mediated by a higher expression of MDM4, a gene located in the common region of gain. MDM4 drives the winner phenotype of the mutant cells in both the undifferentiated and differentiating state by reducing the cells’ sensitivity to DNA damage through decreased p53-mediated apoptosis. Finally, we found that cell density in culture plays a key role in promoting the competitive advantage of the cells by increasing DNA damage.

AB - Gain of 1q is a highly recurrent chromosomal abnormality in human pluripotent stem cells. In this work, we show that gains of 1q impact the differentiation capacity to derivates of the three germ layers, leading to mis-specification to cranial placode and non-neural ectoderm during neuroectoderm differentiation. Also, we found a weaker expression of lineage-specific markers in hepatoblasts and cardiac progenitors. Competition assays show that the cells retain their selective advantage during differentiation, which is mediated by a higher expression of MDM4, a gene located in the common region of gain. MDM4 drives the winner phenotype of the mutant cells in both the undifferentiated and differentiating state by reducing the cells’ sensitivity to DNA damage through decreased p53-mediated apoptosis. Finally, we found that cell density in culture plays a key role in promoting the competitive advantage of the cells by increasing DNA damage.

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M3 - Article

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JO - Cell & Death Disease

JF - Cell & Death Disease

SN - 2041-4889

M1 - 852

ER -

Gain of 1q confers an MDM4-driven growth advantage to undifferentiated and differentiating hESC while altering their differentiation capacity

Abstract

Bibliographical note

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OZRMETH9: The Genetic Component to Infertility and Early Developmental Failure

FWOTM1016: The impact of recurrent chromosomal abnormalities on growth advantage and differentiation capacity of human pluripotent stem cells

FWOTM968: The search for the origin of chromosomal abnormalities in human preimplantation embryos