Large-scale analysis of imprinting in naive human pluripotent stem cells reveals recurrent aberrations and a potential link to FGF signaling

Gal Keshet, Nissim Benvenisty*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Genomic imprinting is a parent-of-origin dependent monoallelic expression of genes. Previous studies showed that conversion of primed human pluripotent stem cells (hPSCs) into naive pluripotency is accompanied by genome-wide loss of methylation that includes imprinted loci. However, the extent of aberrant biallelic expression of imprinted genes is still unknown. Here, we analyze loss of imprinting (LOI) in a large cohort of both bulk and single-cell RNA sequencing samples of naive and primed hPSCs. We show that naive hPSCs exhibit high levels of non-random LOI, with bias toward paternally methylated imprinting control regions. Importantly, we show that different protocols used for the primed to naive conversion led to different extents of LOI, tightly correlated to FGF signaling. This analysis sheds light on the process of LOI occurring during the conversion to naive pluripotency and highlights the importance of these events when modeling disease and development or when utilizing the cells for therapy.

Original languageAmerican English
Pages (from-to)2520-2533
Number of pages14
JournalStem Cell Reports
Volume16
Issue number10
DOIs
StatePublished - 12 Oct 2021

Bibliographical note

Funding Information:
We thank Dr. Ido Sagi and all members of The Azrieli Center for Stem Cells and Genetic Research for their input and critical reading of the manuscript. This work was partially supported by the Israel Science Foundation ( 494/17 ), the Rosetrees Trust , and by Azrieli Foundation . N.B. is the Herbert Cohn Chair in Cancer Research.

Publisher Copyright:
© 2021 The Authors

Keywords

  • epigenetics
  • genomic imprinting
  • human pluripotent stem cells
  • naive pluripotent stem cells

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