Concepedia

Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader–Willi syndromes

Stormy J. Chamberlain, Pin-Fang Chen, Khong Y. Ng, Fany Bourgois-Rocha, Fouad Lemtiri‐Chlieh, Eric S. Levine, Marc Lalande

Proceedings of the National Academy of Sciences · 2010 · 321 citations · 29 references

DOI

TL;DR

Angelman syndrome and Prader–Willi syndrome are neurodevelopmental disorders caused by defects in genomic imprinting, with AS due to loss of UBE3A function and the genetic basis of PWS remaining unknown. The study aims to generate patient‑derived iPSC models to investigate the disease mechanisms of AS and PWS and to examine the timing and mechanism of UBE3A repression during neuronal differentiation. Patient iPSCs were differentiated into neurons, and imprinting status was assessed at the PSW imprinting center and UBE3A locus to evaluate epigenetic stability during reprogramming. The iPSCs retained intact DNA methylation at the PSW imprinting center, and UBE3A imprinting was established during neuronal differentiation with paternal allele silencing and antisense transcript upregulation, mirroring normal brain.

Abstract

Angelman syndrome (AS) and Prader–Willi syndrome (PWS) are neurodevelopmental disorders of genomic imprinting. AS results from loss of function of the ubiquitin protein ligase E3A ( UBE3A ) gene, whereas the genetic defect in PWS is unknown. Although induced pluripotent stem cells (iPSCs) provide invaluable models of human disease, nuclear reprogramming could limit the usefulness of iPSCs from patients who have AS and PWS should the genomic imprint marks be disturbed by the epigenetic reprogramming process. Our iPSCs derived from patients with AS and PWS show no evidence of DNA methylation imprint erasure at the cis -acting PSW imprinting center. Importantly, we find that, as in normal brain, imprinting of UBE3A is established during neuronal differentiation of AS iPSCs, with the paternal UBE3A allele repressed concomitant with up-regulation of the UBE3A antisense transcript. These iPSC models of genomic imprinting disorders will facilitate investigation of the AS and PWS disease processes and allow study of the developmental timing and mechanism of UBE3A repression in human neurons.