Document Type

Article

Version Deposited

Accepted for publication (PostPrint)

Publication Date

7-17-2013

Publication Title

Nature

DOI

http://dx.doi.org/10.1038/nature12394

Abstract

Down syndrome (DS) is a common disorder with enormous medical and social costs, caused by trisomy for chromosome 21 (Chr21). We tested the concept that gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, XIST. Using genome editing with zinc finger nucleases, we targeted a large, inducible XIST transgene into the Chr21 DYRK1A locus, in DS pluripotent stem cells. XIST RNA coats Chr21 and triggers stable heterochromatin modifications, chromosome-wide transcriptional silencing and DNA methylation to form a “Chr21 Barr Body.” This provides a model to study human chromosome inactivation and creates a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Remarkably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing one Chr21. Successful trisomy silencing in vitro also surmounts the major first step towards potential development of “chromosome therapy”.

Comments

This is the Author Manuscript made available for HHS Public Access through PubMedCentral. It was published in final edited form in Nature, 2013 August 15; 500(7462): 296-300 and can be accessed at DOI: 10.1038/nature12394.

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