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Differentiation shifts from a reversible to an irreversible heterochromatin state at the DM1 locus

Author

Listed:
  • Tayma Handal

    (The Eisenberg R&D Authority, Shaare Zedek Medical Center
    The Hebrew University School of Medicine)

  • Sarah Juster

    (The Eisenberg R&D Authority, Shaare Zedek Medical Center
    The Hebrew University School of Medicine)

  • Manar Abu Diab

    (The Eisenberg R&D Authority, Shaare Zedek Medical Center
    The Hebrew University School of Medicine)

  • Shira Yanovsky-Dagan

    (The Eisenberg R&D Authority, Shaare Zedek Medical Center
    The Hebrew University School of Medicine)

  • Fouad Zahdeh

    (Shaare Zedek Medical Center)

  • Uria Aviel

    (The Eisenberg R&D Authority, Shaare Zedek Medical Center
    The Hebrew University School of Medicine)

  • Roni Sarel-Gallily

    (The Hebrew University)

  • Shir Michael

    (The Eisenberg R&D Authority, Shaare Zedek Medical Center
    The Hebrew University School of Medicine)

  • Ester Bnaya

    (The Eisenberg R&D Authority, Shaare Zedek Medical Center
    The Hebrew University School of Medicine)

  • Shulamit Sebban

    (The Hebrew University-Hadassah Medical School)

  • Yosef Buganim

    (The Hebrew University-Hadassah Medical School)

  • Yotam Drier

    (Faculty of Medicine, The Hebrew University)

  • Vincent Mouly

    (Centre de Recherche en Myologie)

  • Stefan Kubicek

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Walther J. A. A. Broek

    (Radboud University Medical Center)

  • Derick G. Wansink

    (Radboud University Medical Center)

  • Silvina Epsztejn-Litman

    (The Eisenberg R&D Authority, Shaare Zedek Medical Center)

  • Rachel Eiges

    (The Eisenberg R&D Authority, Shaare Zedek Medical Center
    The Hebrew University School of Medicine)

Abstract

Epigenetic defects caused by hereditary or de novo mutations are implicated in various human diseases. It remains uncertain whether correcting the underlying mutation can reverse these defects in patient cells. Here we show by the analysis of myotonic dystrophy type 1 (DM1)-related locus that in mutant human embryonic stem cells (hESCs), DNA methylation and H3K9me3 enrichments are completely abolished by repeat excision (CTG2000 expansion), whereas in patient myoblasts (CTG2600 expansion), repeat deletion fails to do so. This distinction between undifferentiated and differentiated cells arises during cell differentiation, and can be reversed by reprogramming of gene-edited myoblasts. We demonstrate that abnormal methylation in DM1 is distinctively maintained in the undifferentiated state by the activity of the de novo DNMTs (DNMT3b in tandem with DNMT3a). Overall, the findings highlight a crucial difference in heterochromatin maintenance between undifferentiated (sequence-dependent) and differentiated (sequence-independent) cells, thus underscoring the role of differentiation as a locking mechanism for repressive epigenetic modifications at the DM1 locus.

Suggested Citation

  • Tayma Handal & Sarah Juster & Manar Abu Diab & Shira Yanovsky-Dagan & Fouad Zahdeh & Uria Aviel & Roni Sarel-Gallily & Shir Michael & Ester Bnaya & Shulamit Sebban & Yosef Buganim & Yotam Drier & Vinc, 2024. "Differentiation shifts from a reversible to an irreversible heterochromatin state at the DM1 locus," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47217-4
    DOI: 10.1038/s41467-024-47217-4
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    1. Ryan Lister & Mattia Pelizzola & Yasuyuki S. Kida & R. David Hawkins & Joseph R. Nery & Gary Hon & Jessica Antosiewicz-Bourget & Ronan O’Malley & Rosa Castanon & Sarit Klugman & Michael Downes & Ruth , 2011. "Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells," Nature, Nature, vol. 471(7336), pages 68-73, March.
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