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Culture-induced recurrent epigenetic aberrations in human pluripotent stem cells

Author

Listed:
  • Uri Weissbein
  • Omer Plotnik
  • Dan Vershkov
  • Nissim Benvenisty

Abstract

Human pluripotent stem cells (hPSCs) are an important player in disease modeling and regenerative medicine. Nonetheless, multiple studies uncovered their inherent genetic instability upon prolonged culturing, where specific chromosomal aberrations provide cells with a growth advantage. These positively selected modifications have dramatic effects on multiple cellular characteristics. Epigenetic aberrations also possess the potential of changing gene expression and altering cellular functions. In the current study we assessed the landscape of DNA methylation aberrations during prolonged culturing of hPSCs, and defined a set of genes which are recurrently hypermethylated and silenced. We further focused on one of these genes, testis-specific Y-encoded like protein 5 (TSPYL5), and demonstrated that when silenced, differentiation-related genes and tumor-suppressor genes are downregulated, while pluripotency- and growth promoting genes are upregulated. This process is similar to the hypermethylation-mediated inactivation of certain genes during tumor development. Our analysis highlights the existence and importance of recurrent epigenetic aberrations in hPSCs during prolonged culturing.Author summary: hPSCs were shown to acquire genetic aberrations during their growth in culture. The aberrations are non-random and positively selected, by altering multiple cellular phenotypes. Similarly to genetic mutations, epigenetic aberrations may also change gene expression levels, leading to altered cellular behaviors, as seen in tumors. In this study we focus on methylation changes, and we showed that there is a set of genes which are recurrently hypermethylated and silenced in high passage cells. One of these genes, TSPYL5, was shown to be downregulated by hypermethylation in multiple cancer types. We showed that upon its silencing in hPSC, differentiation genes and tumor-suppressor genes are downregulated, and pluripotency- and growth promoting genes are upregulated, which drive the positive selection. These results highlight another challenge faced by hPSC in regard to maintenance of intact gene expression program, and emphasize the role of epimutations described in cancer cells also to hPSCs.

Suggested Citation

  • Uri Weissbein & Omer Plotnik & Dan Vershkov & Nissim Benvenisty, 2017. "Culture-induced recurrent epigenetic aberrations in human pluripotent stem cells," PLOS Genetics, Public Library of Science, vol. 13(8), pages 1-16, August.
    • Handle: RePEc:plo:pgen00:1006979
    DOI: 10.1371/journal.pgen.1006979
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    References listed on IDEAS

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    1. Rajagopal, 2014. "The Human Factors," Palgrave Macmillan Books, in: Architecting Enterprise, chapter 9, pages 225-249, Palgrave Macmillan.
    2. Zohar Shipony & Zohar Mukamel & Netta Mendelson Cohen & Gilad Landan & Elad Chomsky & Shlomit Reich Zeliger & Yael Chagit Fried & Elena Ainbinder & Nir Friedman & Amos Tanay, 2014. "Dynamic and static maintenance of epigenetic memory in pluripotent and somatic cells," Nature, Nature, vol. 513(7516), pages 115-119, September.
    3. Uri Ben-David & Gal Arad & Uri Weissbein & Berhan Mandefro & Adva Maimon & Tamar Golan-Lev & Kavita Narwani & Amander T. Clark & Peter W. Andrews & Nissim Benvenisty & Juan Carlos Biancotti, 2014. "Aneuploidy induces profound changes in gene expression, proliferation and tumorigenicity of human pluripotent stem cells," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
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    Cited by:

    1. Moriyah Naama & Moran Rahamim & Valery Zayat & Shulamit Sebban & Ahmed Radwan & Dana Orzech & Rachel Lasry & Annael Ifrah & Mohammad Jaber & Ofra Sabag & Hazar Yassen & Areej Khatib & Silvina Epsztejn, 2023. "Pluripotency-independent induction of human trophoblast stem cells from fibroblasts," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    2. Shiran Bar & Dan Vershkov & Gal Keshet & Elyad Lezmi & Naama Meller & Atilgan Yilmaz & Ofra Yanuka & Malka Nissim-Rafinia & Eran Meshorer & Talia Eldar-Geva & Nissim Benvenisty, 2021. "Identifying regulators of parental imprinting by CRISPR/Cas9 screening in haploid human embryonic stem cells," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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