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. van den Broek; Derick G. Wansink; Silvina Epsztejn-Litman; Rachel Eiges

doi:https://doi.org/10.1038/s41467-024-47217-4

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. van den Broek, Derick G. Wansink, Silvina Epsztejn-Litman, Rachel Eiges

The Hebrew University of Jerusalem

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	3270
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-47217-4
State	Published - Dec 2024

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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https://doi.org/10.1038/s41467-024-47217-4

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Handal, T., Juster, S., Abu Diab, M., Yanovsky-Dagan, S., Zahdeh, F., Aviel, U., Sarel-Gallily, R., Michael, S., Bnaya, E., Sebban, S., Buganim, Y., Drier, Y., Mouly, V., Kubicek, S., van den Broek, W. J. A. A., Wansink, D. G., Epsztejn-Litman, S., & Eiges, R. (2024). Differentiation shifts from a reversible to an irreversible heterochromatin state at the DM1 locus. Nature Communications, 15(1), Article 3270. https://doi.org/10.1038/s41467-024-47217-4

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title = "Differentiation shifts from a reversible to an irreversible heterochromatin state at the DM1 locus",

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.",

author = "Tayma Handal and Sarah Juster and {Abu Diab}, Manar and Shira Yanovsky-Dagan and Fouad Zahdeh and Uria Aviel and Roni Sarel-Gallily and Shir Michael and Ester Bnaya and Shulamit Sebban and Yosef Buganim and Yotam Drier and Vincent Mouly and Stefan Kubicek and {van den Broek}, {Walther J.A.A.} and Wansink, {Derick G.} and Silvina Epsztejn-Litman and Rachel Eiges",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "https://doi.org/10.1038/s41467-024-47217-4",

language = "الإنجليزيّة",

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Handal, T, Juster, S, Abu Diab, M, Yanovsky-Dagan, S, Zahdeh, F, Aviel, U, Sarel-Gallily, R, Michael, S, Bnaya, E, Sebban, S, Buganim, Y , Drier, Y, Mouly, V, Kubicek, S, van den Broek, WJAA, Wansink, DG, Epsztejn-Litman, S & Eiges, R 2024, 'Differentiation shifts from a reversible to an irreversible heterochromatin state at the DM1 locus', Nature Communications, vol. 15, no. 1, 3270. https://doi.org/10.1038/s41467-024-47217-4

TY - JOUR

T1 - Differentiation shifts from a reversible to an irreversible heterochromatin state at the DM1 locus

AU - Handal, Tayma

AU - Juster, Sarah

AU - Abu Diab, Manar

AU - Yanovsky-Dagan, Shira

AU - Zahdeh, Fouad

AU - Aviel, Uria

AU - Sarel-Gallily, Roni

AU - Michael, Shir

AU - Bnaya, Ester

AU - Sebban, Shulamit

AU - Buganim, Yosef

AU - Drier, Yotam

AU - Mouly, Vincent

AU - Kubicek, Stefan

AU - van den Broek, Walther J.A.A.

AU - Wansink, Derick G.

AU - Epsztejn-Litman, Silvina

AU - Eiges, Rachel

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

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U2 - https://doi.org/10.1038/s41467-024-47217-4

DO - https://doi.org/10.1038/s41467-024-47217-4

M3 - مقالة

C2 - 38627364

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3270

ER -

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

Abstract

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