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

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, Vincent Mouly, Stefan Kubicek, Walther J. A. A. Broek, Derick G. Wansink (), Silvina Epsztejn-Litman and Rachel Eiges ()
Additional contact information
Tayma Handal: The Eisenberg R&D Authority, Shaare Zedek Medical Center
Sarah Juster: The Eisenberg R&D Authority, Shaare Zedek Medical Center
Manar Abu Diab: The Eisenberg R&D Authority, Shaare Zedek Medical Center
Shira Yanovsky-Dagan: The Eisenberg R&D Authority, Shaare Zedek Medical Center
Fouad Zahdeh: Shaare Zedek Medical Center
Uria Aviel: The Eisenberg R&D Authority, Shaare Zedek Medical Center
Roni Sarel-Gallily: The Hebrew University
Shir Michael: The Eisenberg R&D Authority, Shaare Zedek Medical Center
Ester Bnaya: The Eisenberg R&D Authority, Shaare Zedek Medical Center
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

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47217-4

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