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

• Published in: Nature communications 2024-04, Vol.15 (1), p.3270-3270, Article 3270
• Main Authors: Handal, Tayma, Juster, Sarah, Abu Diab, Manar, Yanovsky-Dagan, Shira, Zahdeh, Fouad, Aviel, Uria, Sarel-Gallily, Roni, Michael, Shir, Bnaya, Ester, Sebban, Shulamit, Buganim, Yosef, Drier, Yotam, Mouly, Vincent, Kubicek, Stefan, van den Broek, Walther J. A. A., Wansink, Derick G., Epsztejn-Litman, Silvina, Eiges, Rachel
• Format: Article
• Language: English
• Subjects: 13/100; 38; 38/15; 38/22; 38/23; 38/77; 42/41; 631/208/176/1988; 631/532/2117; Cell differentiation; Cell Differentiation - genetics; Defects; Differentiation (biology); DNA Methylation; Dystrophy; Embryo cells; Epigenesis, Genetic; Epigenetics; Genetic modification; Genome editing; Heterochromatin; Heterochromatin - genetics; Humanities and Social Sciences; Humans; multidisciplinary; Mutants; Mutation; Myoblasts; Myotonic dystrophy; Myotonic Dystrophy - genetics; Science; Science (multidisciplinary); Stem cells
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47217-4

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. Gene-editing at the DM1 mutant locus revealed a fundamental difference between undifferentiated and differentiated cell states: abnormal epigenetic modifications cannot be repaired after differentiation.