Translating dosage compensation to trisomy 21
Department of Cell and Developmental Biology
Medical Subject Headings
Down Syndrome; RNA, Long Untranslated; X Chromosome Inactivation; Gene Silencing; Genetic Therapy
Cell Biology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Developmental Biology | Genetics and Genomics | Therapeutics
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'.
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Citation: Nature. 2013 Aug 15;500(7462):296-300. doi: 10.1038/nature12394. Epub 2013 Jul 17. Link to article on publisher's website
Jiang, Jun; Jing, Yuanchun; Cost, Gregory J.; Chiang, Jen-Chieh; Kolpa, Heather J.; Cotton, Allison M.; Carone, Dawn M.; Carone, Benjamin R.; Shivak, David A.; Guschin, Dmitry Y.; Pearl, Jocelynn R.; Rebar, Edward J.; Byron, Meg; Gregory, Philip D.; Brown, Carolyn J.; Urnov, Fyodor D.; Hall, Lisa L.; and Lawrence, Jeanne B., "Translating dosage compensation to trisomy 21" (2013). Lawrence Lab Publications. 9.