title: Uncovering the Role of Hypermethylation by CTG Expansion in Myotonic Dystrophy Type 1 Using Mutant Human Embryonic Stem Cells.
abstract: CTG repeat expansion in DMPK, the cause of myotonic dystrophy type 1 (DM1), frequently results in hypermethylation and reduced SIX5 expression. The contribution of hypermethylation to disease pathogenesis and the precise mechanism by which SIX5 expression is reduced are unknown. Using 14 different DM1-affected human embryonic stem cell (hESC) lines, we characterized a differentially methylated region (DMR) near the CTGs. This DMR undergoes hypermethylation as a function of expansion size in a way that is specific to undifferentiated cells and is associated with reduced SIX5 expression. Using functional assays, we provide evidence for regulatory activity of the DMR, which is lost by hypermethylation and may contribute to DM1 pathogenesis by causing SIX5 haplo-insufficiency. This study highlights the power of hESCs in disease modeling and describes a DMR that functions both as an exon coding sequence and as a regulatory element whose activity is epigenetically hampered by a heritable mutation.
authors.affiliation: Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Yanovsky-Dagan
authors.affiliation: Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Avitzour
authors.affiliation: Zohar PGD Lab, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel.
authors.forename: Gheona
authors.initials: G
authors.lastname: Altarescu
authors.affiliation: Zohar PGD Lab, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel.
authors.forename: Paul
authors.initials: P
authors.lastname: Renbaum
authors.affiliation: IVF Unit, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel.
authors.forename: Talia
authors.initials: T
authors.lastname: Eldar-Geva
authors.affiliation: IVF Unit, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel.
authors.forename: Oshrat
authors.initials: O
authors.lastname: Schonberger
authors.affiliation: Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem 91240, Israel.
authors.forename: Stella
authors.initials: S
authors.lastname: Mitrani-Rosenbaum
authors.affiliation: Zohar PGD Lab, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel.
authors.forename: Ephrat
authors.initials: E
authors.lastname: Levy-Lahad
authors.affiliation: Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors.forename: Ramon Y
authors.initials: RY
authors.lastname: Birnbaum
authors.affiliation: Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Gepstein
authors.affiliation: Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel.
authors.forename: Silvina
authors.initials: S
authors.lastname: Epsztejn-Litman
authors.affiliation: Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel. Electronic address: rachela@szmc.org.il.
authors.forename: Rachel
authors.initials: R
authors.lastname: Eiges
mesh_terms: D018899:CpG Islands; D019175:DNA Methylation; D042622:DNA Repeat Expansion; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009223:Myotonic Dystrophy / Q000235:genetics*; D065636:Myotonin-Protein Kinase / Q000235:genetics*
chemical_list: C585517:DMPK protein, human; D018398:Homeodomain Proteins; C106687:SIX5 protein, human; D065636:Myotonin-Protein Kinase