Imprinting fidelity in mouse iPSCs depends on sex of donor cell and medium formulation

Maria Arez, Melanie Eckersley-Maslin, Tajda Klobučar, João Gilsa Lopes, Felix Krueger, Annalisa Mupo, Ana Cláudia Raposo, David Oxley, Samantha Mancino, Anne-Valerie Gendrel, Bruno Bernardes de Jesus and Simão Teixeira da Rocha ()
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Maria Arez: Universidade de Lisboa
Melanie Eckersley-Maslin: Babraham Institute
Tajda Klobučar: Universidade de Lisboa
João Gilsa Lopes: Universidade de Lisboa
Felix Krueger: Babraham Institute
Annalisa Mupo: Babraham Institute
Ana Cláudia Raposo: Universidade de Lisboa
David Oxley: The Babraham Institute
Samantha Mancino: Universidade de Lisboa
Anne-Valerie Gendrel: Universidade de Lisboa
Bruno Bernardes de Jesus: Universidade de Lisboa
Simão Teixeira da Rocha: Universidade de Lisboa

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Reprogramming of somatic cells into induced Pluripotent Stem Cells (iPSCs) is a major leap towards personalised approaches to disease modelling and cell-replacement therapies. However, we still lack the ability to fully control the epigenetic status of iPSCs, which is a major hurdle for their downstream applications. Epigenetic fidelity can be tracked by genomic imprinting, a phenomenon dependent on DNA methylation, which is frequently perturbed in iPSCs by yet unknown reasons. To try to understand the causes underlying these defects, we conducted a thorough imprinting analysis using IMPLICON, a high-throughput method measuring DNA methylation levels, in multiple female and male murine iPSC lines generated under different experimental conditions. Our results show that imprinting defects are remarkably common in iPSCs, but their nature depends on the sex of donor cells and their response to culture conditions. Imprints in female iPSCs resist the initial genome-wide DNA demethylation wave during reprogramming, but ultimately cells accumulate hypomethylation defects irrespective of culture medium formulations. In contrast, imprinting defects on male iPSCs depends on the experimental conditions and arise during reprogramming, being mitigated by the addition of vitamin C (VitC). Our findings are fundamental to further optimise reprogramming strategies and generate iPSCs with a stable epigenome.

Date: 2022
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DOI: 10.1038/s41467-022-33013-5

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