The Isochromosome 20q Abnormality of Pluripotent Cells Interrupts Germ Layer Differentiation

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2023 Feb 21

PMID 36801002

Authors

Loriana Vitillo

Fabiha Anjum

Zoe Hewitt

Dylan Stavish

Owen Laing

Duncan Baker

Ivana Barbaric

Pete Coffey

Affiliations

Soon will be listed here.

Abstract

Chromosome 20 abnormalities are some of the most frequent genomic changes acquired by human pluripotent stem cell (hPSC) cultures worldwide. Yet their effects on differentiation remain largely unexplored. We investigated a recurrent abnormality also found on amniocentesis, the isochromosome 20q (iso20q), during a clinical retinal pigment epithelium differentiation. Here we show that the iso20q abnormality interrupts spontaneous embryonic lineage specification. Isogenic lines revealed that under conditions that promote the spontaneous differentiation of wild-type hPSCs, the iso20q variants fail to differentiate into primitive germ layers and to downregulate pluripotency networks, resulting in apoptosis. Instead, iso20q cells are highly biased for extra-embryonic/amnion differentiation following inhibition of DNMT3B methylation or BMP2 treatment. Finally, directed differentiation protocols can overcome the iso20q block. Our findings reveal in iso20q a chromosomal abnormality that impairs the developmental competency of hPSCs toward germ layers but not amnion, which models embryonic developmental bottlenecks in the presence of aberrations.

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