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Deletion of the CTG Expansion in Myotonic Dystrophy Type 1 Reverses DMPK Aberrant Methylation in Human Embryonic Stem Cells but not Affected Myoblasts

Shira Yanovsky-Dagan, Ester Bnaya, Manar Abu Diab, Tayma Handal, Fouad Zahdeh, Walther J.A.A. van den Broek, Silvina Epsztejn-Litman, Derick G. Wansink, Rachel Eiges
doi: https://doi.org/10.1101/631457
Shira Yanovsky-Dagan
1Stem Cell Research Laboratory, Shaare Zedek Medical Center, Jerusalem 91031, Israel
2The Hebrew University School of Medicine, Jerusalem 91120, Israel
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Ester Bnaya
1Stem Cell Research Laboratory, Shaare Zedek Medical Center, Jerusalem 91031, Israel
2The Hebrew University School of Medicine, Jerusalem 91120, Israel
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Manar Abu Diab
1Stem Cell Research Laboratory, Shaare Zedek Medical Center, Jerusalem 91031, Israel
2The Hebrew University School of Medicine, Jerusalem 91120, Israel
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Tayma Handal
1Stem Cell Research Laboratory, Shaare Zedek Medical Center, Jerusalem 91031, Israel
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Fouad Zahdeh
3Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem 91031, Israel
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Walther J.A.A. van den Broek
4Department of Cell Biology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands
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Silvina Epsztejn-Litman
1Stem Cell Research Laboratory, Shaare Zedek Medical Center, Jerusalem 91031, Israel
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Derick G. Wansink
4Department of Cell Biology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands
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  • For correspondence: rachela@szmc.org.il
Rachel Eiges
1Stem Cell Research Laboratory, Shaare Zedek Medical Center, Jerusalem 91031, Israel
2The Hebrew University School of Medicine, Jerusalem 91120, Israel
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  • For correspondence: rachela@szmc.org.il
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ABSTRACT

Myotonic dystrophy type 1 (DM1) results from a CTG repeat expansion in the 3’-UTR of DMPK. When the repeat extensively expands, this results in DMPK aberrant methylation, reduction in SIX5 transcription and the development of the congenital form of the disease. To explore whether hypermethylation could be reversed in DM1 embryonic stem cells (hESCs) and patient myoblasts, we monitored methylation levels following removal of the expanded repeat by CRISPR/Cas9-mediated editing. Excision of the repeat in undifferentiated hESCs (CTG2000) resets the locus by abolishing abnormal methylation and H3K9me3 enrichment, and rescues SIX5 transcription. In contrast, in affected myoblasts methylation levels remain unchanged following deletion of a large expansion (CTG2600). Altogether, this provides evidence for a transition from a reversible to an irreversible heterochromatin state by the DM1 mutation upon cell differentiation. These findings should be taken into account when considering gene correction in congenital DM1 and potentially other epigenetically regulated disorders.

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Posted May 08, 2019.
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Deletion of the CTG Expansion in Myotonic Dystrophy Type 1 Reverses DMPK Aberrant Methylation in Human Embryonic Stem Cells but not Affected Myoblasts
Shira Yanovsky-Dagan, Ester Bnaya, Manar Abu Diab, Tayma Handal, Fouad Zahdeh, Walther J.A.A. van den Broek, Silvina Epsztejn-Litman, Derick G. Wansink, Rachel Eiges
bioRxiv 631457; doi: https://doi.org/10.1101/631457
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Deletion of the CTG Expansion in Myotonic Dystrophy Type 1 Reverses DMPK Aberrant Methylation in Human Embryonic Stem Cells but not Affected Myoblasts
Shira Yanovsky-Dagan, Ester Bnaya, Manar Abu Diab, Tayma Handal, Fouad Zahdeh, Walther J.A.A. van den Broek, Silvina Epsztejn-Litman, Derick G. Wansink, Rachel Eiges
bioRxiv 631457; doi: https://doi.org/10.1101/631457

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