Biology subjects

Couvreu de Deckersberg, E.

Publications and source records attributed to Couvreu de Deckersberg, E..

3 recordsLinked to original sources

bioRxiv2023

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

Gains of 1q are 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 miss-specification to cranial placode and non-neural ectoderm during neuroectoderm differentiation and by poorer 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 find that cell density in culture plays a key role in promoting the competitive advantage of the cells by increasing DNA damage.

cell biology↗

bioRxiv2023

SALL3 mediates the loss of neuroectodermal differentiation potential in human embryonic stem cells with chromosome 18q loss

Human pluripotent stem cell (hPSC) cultures are prone to genetic drift, as cells that have acquired specific genetic abnormalities experience a selective advantage in vitro. These abnormalities are highly recurrent in hPSC lines worldwide, but currently their functional consequences in differentiating cells are scarcely described. An accurate assessment of the risk associated with these genetic variants in both research and clinical settings is therefore lacking. In this work, we established that one of these recurrent abnormalities, the loss of chromosome 18q, impairs neuroectoderm commitment and affects the cardiac progenitor differentiation of hESCs. We show that downregulation of SALL3, a gene located in the common 18q loss region, is responsible for failed neuroectodermal differentiation. Knockdown of SALL3 in control lines impaired differentiation in a manner similar to the loss of 18q, while transgenic overexpression of SALL3 in hESCs with 18q loss rescued the differentiation capacity of the cells. Finally, we show by gene expression analysis that loss of 18q and downregulation of SALL3 leads to changes in the expression of genes involved in pathways regulating pluripotency and differentiation, including the WNT, NOTCH, JAK-STAT, TGF-beta and NF-kB pathways, suggesting that these cells are in an altered state of pluripotency.

cell biology↗

bioRxiv2021

Mitochondrial DNA variants segregate during human preimplantation development into genetically different cell lineages that are maintained postnatally

Humans present remarkable mitochondrial DNA (mtDNA) variant mosaicism, not only across tissues but even across individual cells within one person. The timing of the first appearance of this mosaicism has not yet been established. In this study, we hypothesized it occurs during preimplantation development. To investigate this, we deep-sequenced the mtDNA of 254 oocytes from 85 donors, 158 single blastomeres of 25 day-3 embryos, 17 inner cell mass and trophectoderm samples of 7 day-5 blastocysts, 142 bulk DNA and 68 single cells of different adult tissues. We found that day-3 preimplantation embryos already present blastomeres that carry variants unique to that cell, showing that the first events of mtDNA mosaicism happen very early in human development. We classified the mtDNA variants based on their recurrence or uniqueness across sibling oocytes and embryos, and between single cells and samples from the same embryos or adult individuals. Variants that recurred across samples had higher heteroplasmic loads and more frequently resulted in synonymous changes or were located in non-coding regions than variants that were unique to one oocyte or single embryonic cell. These differences were maintained through developmental stages, suggesting that the mtDNA mosaicism arising in preimplantation development is maintained into adulthood. Further, the results support a model in which close clustering of mitochondria carrying specific mtDNA variants in the ooplasm leads to asymmetric distribution of these mitochondria throughout the cell divisions of the preimplantation embryo, resulting in the appearance of the first form of mtDNA mosaicism in human development.

genetics↗