Translating dosage compensation to trisomy 21

Jun Jiang, Yuanchun Jing, Gregory J. Cost, Jen-Chieh Chiang, Heather J. Kolpa, Allison M. Cotton, Dawn M. Carone, Benjamin R. Carone, David A. Shivak, Dmitry Y. Guschin, Jocelynn R. Pearl, Edward J. Rebar, Meg Byron, Philip D. Gregory, Carolyn J. Brown, Fyodor D. Urnov (), Lisa L. Hall and Jeanne B. Lawrence ()
Additional contact information
Jun Jiang: University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA
Yuanchun Jing: University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA
Gregory J. Cost: Sangamo BioSciences, 501 Canal Boulevard
Jen-Chieh Chiang: University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA
Heather J. Kolpa: University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA
Allison M. Cotton: University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada
Dawn M. Carone: University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA
Benjamin R. Carone: University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA
David A. Shivak: Sangamo BioSciences, 501 Canal Boulevard
Dmitry Y. Guschin: Sangamo BioSciences, 501 Canal Boulevard
Jocelynn R. Pearl: Sangamo BioSciences, 501 Canal Boulevard
Edward J. Rebar: Sangamo BioSciences, 501 Canal Boulevard
Meg Byron: University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA
Philip D. Gregory: Sangamo BioSciences, 501 Canal Boulevard
Carolyn J. Brown: University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada
Fyodor D. Urnov: Sangamo BioSciences, 501 Canal Boulevard
Lisa L. Hall: University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA
Jeanne B. Lawrence: University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA

Nature, 2013, vol. 500, issue 7462, 296-300

Abstract: Abstract Down’s syndrome is a common disorder with enormous medical and social costs, caused by trisomy for chromosome 21. We tested the concept that gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, XIST (the X-inactivation gene). Using genome editing with zinc finger nucleases, we inserted a large, inducible XIST transgene into the DYRK1A locus on chromosome 21, in Down’s syndrome pluripotent stem cells. The XIST non-coding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosome-wide transcriptional silencing and DNA methylation to form a ‘chromosome 21 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. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing one chromosome 21. Successful trisomy silencing in vitro also surmounts the major first step towards potential development of ‘chromosome therapy’.

Date: 2013
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DOI: 10.1038/nature12394

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