TY - JOUR
T1 - Uncovering the Role of Hypermethylation by CTG Expansion in Myotonic Dystrophy Type 1 Using Mutant Human Embryonic Stem Cells
AU - Yanovsky-Dagan, Shira
AU - Avitzour, Michal
AU - Altarescu, Gheona
AU - Renbaum, Paul
AU - Eldar-Geva, Talia
AU - Schonberger, Oshrat
AU - Mitrani-Rosenbaum, Stella
AU - Levy-Lahad, Ephrat
AU - Birnbaum, Ramon Y.
AU - Gepstein, Lior
AU - Epsztejn-Litman, Silvina
AU - Eiges, Rachel
N1 - Funding Information:
We thank Dr. Amira Gepstein for assistance with in vitro cardiac differentiation, Dr. David Zeevi for critical reading of the manuscript, Dr. Dalit Ben-Yosef for the provision of the LIS-DM-affected hESC line, Prof. Douglas Melton and Prof. Nissim Benvenisty for the provision of WT hESC lines (HES13, HES-B123, and HES-B200), and Dr. Micha Mandel for assistance with the statistical analysis. This work was partly supported by the Israel Science Foundation (to E.R., grant 711/12), a donation from the Abrasba Foundation (to E.R., Gindi family), and a Career Integration Grant (to B.R., grant 630849).
Publisher Copyright:
© 2015 The Authors.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84954164925&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2015.06.003
DO - 10.1016/j.stemcr.2015.06.003
M3 - Article
AN - SCOPUS:84954164925
SN - 2213-6711
VL - 5
SP - 221
EP - 231
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 2
ER -
