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The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome

Nature Genetics volume 46, pages 551557 (2014) | Download Citation


Parental imprinting is a form of epigenetic regulation that results in parent-of-origin differential gene expression. To study Prader-Willi syndrome (PWS), a developmental imprinting disorder, we generated case-derived induced pluripotent stem cells (iPSCs) harboring distinct aberrations in the affected region on chromosome 15. In studying PWS-iPSCs and human parthenogenetic iPSCs, we unexpectedly found substantial upregulation of virtually all maternally expressed genes (MEGs) in the imprinted DLK1-DIO3 locus on chromosome 14. Subsequently, we determined that IPW, a long noncoding RNA in the critical region of the PWS locus, is a regulator of the DLK1-DIO3 region, as its overexpression in PWS and parthenogenetic iPSCs resulted in downregulation of MEGs in this locus. We further show that gene expression changes in the DLK1-DIO3 region coincide with chromatin modifications rather than DNA methylation levels. Our results suggest that a subset of PWS phenotypes may arise from dysregulation of an imprinted locus distinct from the PWS region.

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Fibroblasts obtained from an individual with PWS harboring complete mUPD of chromosome 15 were kindly donated by V. Gross-Tsur (Multidisciplinary Prader-Willi Syndrome Clinic, Child Neurology Unit, Shaare Zedek Medical Center). This research was partially funded by the Israel Science Foundation–Morasha Foundation (grant 1252/12) and by the Israel Ministry of Science and Technology Infrastructure (grant 3-9693).

Author information


  1. Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.

    • Yonatan Stelzer
    • , Ido Sagi
    • , Ofra Yanuka
    •  & Nissim Benvenisty
  2. Stem Cell Research Laboratory, Shaare Zedek Medical Center, The Hebrew University, Jerusalem, Israel.

    • Rachel Eiges


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Y.S. contributed to the conception and design of the study, the collection and assembly of data, data analysis and interpretation, and manuscript writing. I.S. contributed to the collection and assembly of data and graphic design. O.Y. and R.E. contributed to the collection and assembly of data. N.B. contributed to the conception and design of the study, financial support, data analysis and interpretation, and manuscript writing.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nissim Benvenisty.

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