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bioRxiv · 10.1101/2023.06.26.546513

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

Spits, C.·Lei, Y.·Al Delbany, D.·Krivec, N.·Regin, M.·Couvreu de Deckersberg, E.·Janssens, C.·Ghosh, M.·Sermon, K. D.
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Abstract

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.

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Spits, C., Lei, Y., Al Delbany, D., Krivec, N., Regin, M., Couvreu de Deckersberg, E., Janssens, C., Ghosh, M., Sermon, K. D.. 2023-06-26. SALL3 mediates the loss of neuroectodermal differentiation potential in human embryonic stem cells with chromosome 18q loss. https://doi.org/10.1101/2023.06.26.546513

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