title: Translating dosage compensation to trisomy 21.
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'.
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Jiang
authors.forename: Yuanchun
authors.initials: Y
authors.lastname: Jing
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cost
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Chiang
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Kolpa
authors.forename: Allison M
authors.initials: AM
authors.lastname: Cotton
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Carone
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Carone
authors.forename: David A
authors.initials: DA
authors.lastname: Shivak
authors.forename: Dmitry Y
authors.initials: DY
authors.lastname: Guschin
authors.forename: Jocelynn R
authors.initials: JR
authors.lastname: Pearl
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Rebar
authors.forename: Meg
authors.initials: M
authors.lastname: Byron
authors.forename: Philip D
authors.initials: PD
authors.lastname: Gregory
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Brown
authors.forename: Fyodor D
authors.initials: FD
authors.lastname: Urnov
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Hall
authors.forename: Jeanne B
authors.initials: JB
authors.lastname: Lawrence
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D019175:DNA Methylation; D004303:Dosage Compensation, Genetic; D004314:Down Syndrome / Q000235:genetics* / Q000628:therapy; D020868:Gene Silencing; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008297:Male; D051379:Mice; D016254:Mutagenesis, Insertional; D055495:Neurogenesis; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012728:Sex Chromatin / Q000235:genetics; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: D062085:RNA, Long Noncoding; C077885:XIST non-coding RNA