Gain of 1q Confers an MDM4-driven Growth Advantage to Undifferentiated and Differentiating HESC While Altering Their Differentiation Capacity

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2024 Nov 21

PMID 39572522

Authors

Nusa Krivec

Edouard Couvreu de Deckersberg

Yingnan Lei

Diana Al Delbany

Marius Regin

Stefaan Verhulst

Leo A van Grunsven

Karen Sermon

Claudia Spits

Affiliations

Soon will be listed here.

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.

Citing Articles

Culture-acquired genetic variation in human pluripotent stem cells: Twenty years on.

Vales J, Barbaric I Bioessays. 2024; 46(12):e2400062.

PMID: 38873900 PMC: 11589660. DOI: 10.1002/bies.202400062.

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