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

Authors:
Dr. Yonatan Stelzer, PhD
Dr. Yonatan Stelzer, PhD
Whitehead Institute, MIT
Postdoctoral Fellow
Cambridge, MA | United States
Ido Sagi
Ido Sagi
Silberman Institute of Life Sciences
Israel
Ofra Yanuka
Ofra Yanuka
The Hebrew University
Israel
Rachel Eiges
Rachel Eiges
The Hebrew University
Israel
Nissim Benvenisty
Nissim Benvenisty
The Hebrew University
Israel

Nat Genet 2014 Jun 11;46(6):551-7. Epub 2014 May 11.

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

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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http://dx.doi.org/10.1038/ng.2968DOI Listing
June 2014
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